Submissions for variant NM_000492.4(CFTR):c.4242+13A>G

gnomAD frequency: 0.00295  dbSNP: rs76179227

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079005	SCV000110874	benign	not specified	2013-04-29	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000079005	SCV000270059	benign	not specified	2017-07-31	criteria provided, single submitter	clinical testing	c.4242+13A>G in intron 26 of CFTR: This variant is not expected to have clinical significance because it has been identified in 1.6% (159/10116) of Ashkenazi Je wish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broa dinstitute.org; dbSNP rs76179227). It was also identified in 5 homozygotes in gn omAD.
Invitae	RCV000987967	SCV000285006	benign	Cystic fibrosis	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000079005	SCV000304496	likely benign	not specified		criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587429	SCV000603039	benign	not provided	2023-07-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587429	SCV000697015	benign	not provided	2016-06-28	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.4242+13A>G variant involves the alteration of a non-conserved intronic nucleotide at a position not widely known to affect normal splicing. One in silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict the variant not to affect splicing, and this prediction is supported by a minigene splicing assay showing no abnormal RNA products from a minigene containing this intronic variant. This variant was found in 424/120694 control chromosomes (including 1 homozygote), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0051196 (333/65044). This frequency is less than the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603), and it cannot be ruled out that the homozygote could be affected since the ExAC cohort is a general population cohort rather than a healthy or disease-free cohort. Although this variant is found at a frequency less than the most common pathogenic CFTR variant, DeltaF508 (allele frequency in ExAC of 823/121296), c.4242+13A>G is found at a frequency greater than 2-fold higher than the second most common pathogenic CFTR variant in ExAC, c.350G>A (p.Arg117His; 185/120360), highly suggesting that c.4242+13A>G is not pathogenic.Although the variant has been found in patients reported in the literature, there are no reports that show the variants clear-cut causal role in CF and/or CBAVD. In other CFTR-RD phenotypes (asthma, DB, and COPD), this variant was observed at similar frequencies in cases and controls, supporting the notion that it is not a risk factor for these milder phenotypes either. To our knowledge, there was only one report of the variant co-occurring with a pathogenic variant, c.5T_TG11, in a diffuse bronchiectasis patient; however, c.-1043dupT (not in ClinVar and not yet internally classified) was also identified in this patient, phase of these variants was not specified, segregation studies were not performed, and authors consider the variant of interest to be a polymorphism since functional studies showed no effect on splicing (Bergougnoux_JCF_2015). Additionally, UMD reports the variant as a complex allele with c.2538G>A (p.Trp846X) and c.1521_1523delCTT (p.Phe508del) on the other allele in an individual with CF (unpublished reference), suggesting that the variant of interest is not causative in this patient. Furthermore, multiple papers as well as Emory Genetics lab via ClinVar and SickKids report the variant as a benign polymorphism. Taken together, this intronic CFTR variant has been classified as Benign.
Mendelics	RCV000987967	SCV001137500	benign	Cystic fibrosis	2019-05-28	criteria provided, single submitter	clinical testing
CFTR-France	RCV000987967	SCV001169177	benign	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation	the variant does not result in CFTR-RD neither
Illumina Laboratory Services, Illumina	RCV001160217	SCV001322000	benign	CFTR-related disorders	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587429	SCV002047322	benign	not provided	2021-03-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002256040	SCV002529726	likely benign	Hereditary pancreatitis	2021-05-17	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000587429	SCV002545550	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	CFTR: BS2
Genetics and Molecular Pathology, SA Pathology	RCV000987967	SCV002556536	likely benign	Cystic fibrosis	2019-06-26	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000987967	SCV002574095	benign	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: BS2, BS3, BP4
Ambry Genetics	RCV000987967	SCV002629774	benign	Cystic fibrosis	2014-12-24	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Natera, Inc.	RCV000987967	SCV001456318	benign	Cystic fibrosis	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000079005	SCV001926317	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000079005	SCV001971470	benign	not specified		no assertion criteria provided	clinical testing