Submissions for variant NM_015559.3(SETBP1):c.1037C>T (p.Thr346Ile)

gnomAD frequency: 0.00003  dbSNP: rs557430935

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001559700	SCV001781989	likely benign	not provided	2020-10-08	criteria provided, single submitter	clinical testing
Invitae	RCV001559700	SCV002457344	benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002502259	SCV002806653	likely benign	Schinzel-Giedion syndrome; Intellectual disability, autosomal dominant 29	2021-11-18	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003316486	SCV004015437	likely benign	Schinzel-Giedion syndrome	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001559700	SCV004143006	benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	SETBP1: BP4, BS1, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357895	SCV001553495	benign	not specified		no assertion criteria provided	clinical testing	The SETBP1 p.Thr346Ile variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs557430935), Cosmic and ClinVar (classified as likely benign by Illumina for Schinzel-Giedion Midface Retraction Syndrome). The variant was identified in control databases in 364 of 280308 chromosomes (4 homozygous) at a frequency of 0.001299 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 340 of 30552 chromosomes (freq: 0.01113), Other in 6 of 7168 chromosomes (freq: 0.000837), Latino in 13 of 35364 chromosomes (freq: 0.000368), East Asian in 1 of 19910 chromosomes (freq: 0.00005), African in 1 of 24702 chromosomes (freq: 0.00004) and European (non-Finnish) in 3 of 127220 chromosomes (freq: 0.000024), but was not observed in the Ashkenazi Jewish or European (Finnish) populations. The p.Thr346 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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 this variant meets our laboratory's criteria to be classified as benign.