Submissions for variant NM_000307.5(POU3F4):c.139C>T (p.Pro47Ser)

gnomAD frequency: 0.00110  dbSNP: rs144417952

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155384	SCV000205071	likely benign	not specified	2012-05-07	criteria provided, single submitter	clinical testing	p.Pro47Ser in Exon 1 of POU3F4: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (14/3216) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS; dbSNP rs144417952).
Illumina Laboratory Services, Illumina	RCV000315718	SCV000482835	benign	X-linked mixed hearing loss with perilymphatic gusher	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000966116	SCV001113404	benign	not provided	2024-01-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000966116	SCV001881340	benign	not provided	2019-03-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000966116	SCV001553607	likely benign	not provided		no assertion criteria provided	clinical testing	The POU3F4 p.Pro47Ser variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs144417952) and ClinVar (classified as likely benign by Laboratory for Molecular Medicine and Illumina). The variant was also identified in control databases in 97 of 198285 chromosomes (26 hemizygous) at a frequency of 0.000489 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 76 of 18537 chromosomes (freq: 0.0041), Latino in 7 of 27514 chromosomes (freq: 0.000254) and European (non-Finnish) in 14 of 88908 chromosomes (freq: 0.000158), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The p.Pro47 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003965163	SCV004785190	benign	POU3F4-related disorder	2019-08-27	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).