rs199979628
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PS1_ModerateBP4BS2
The NM_006080.3(SEMA3A):c.196C>T(p.Arg66Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000695 in 1,613,752 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Consequence
NM_006080.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SEMA3A | NM_006080.3 | c.196C>T | p.Arg66Trp | missense_variant | 2/17 | ENST00000265362.9 | |
SEMA3A | XM_005250110.4 | c.196C>T | p.Arg66Trp | missense_variant | 5/20 | ||
SEMA3A | XM_047419751.1 | c.196C>T | p.Arg66Trp | missense_variant | 6/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SEMA3A | ENST00000265362.9 | c.196C>T | p.Arg66Trp | missense_variant | 2/17 | 1 | NM_006080.3 | P1 | |
SEMA3A | ENST00000436949.5 | c.196C>T | p.Arg66Trp | missense_variant | 3/18 | 5 | P1 | ||
SEMA3A | ENST00000420047.1 | c.196C>T | p.Arg66Trp | missense_variant | 3/5 | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.000394 AC: 60AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000525 AC: 132AN: 251190Hom.: 0 AF XY: 0.000545 AC XY: 74AN XY: 135746
GnomAD4 exome AF: 0.000726 AC: 1061AN: 1461498Hom.: 1 Cov.: 30 AF XY: 0.000726 AC XY: 528AN XY: 727086
GnomAD4 genome ? AF: 0.000394 AC: 60AN: 152254Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31AN XY: 74430
ClinVar
Submissions by phenotype
not provided Uncertain:2Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 12, 2021 | Identified in patients with Kallmann syndrome, some of whom harbored variants in other genes (Hanchate et al., 2012; Cassatella et al., 2018; Bouilly et al., 2018); Identified in a patient with CHARGE syndrome who was negative for variants in the CHD7 gene; this variant was inherited from a healthy father and was hypothesized to have a modifier role (Schultz et al., 2014); Reported in an individual with unilateral vesicoureteric reflux (Nicolaou et al., 2016), and in one case with sudden unexplained death (Neubauer et al., 2018), however, familial segregation studies were not included in these studies; Published functional studies demonstrate that this variant results in impaired semaphorin-3A secretion (Hanchate et al., 2012; Ufartes et al., 2018); This variant is associated with the following publications: (PMID: 32171629, 33895855, 22927827, 29419413, 29350269, 24728844, 26489027, 29202173, 30098700, 29432577) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 01, 2023 | An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects SEMA3A function (PMID: 22927827). ClinVar contains an entry for this variant (Variation ID: 68832). This missense change has been observed in individual(s) with SEMA3A-related conditions (PMID: 22927827, 24728844, 29419413, 30098700). This variant is present in population databases (rs199979628, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 66 of the SEMA3A protein (p.Arg66Trp). - |
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
SEMA3A-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 26, 2023 | The SEMA3A c.196C>T variant is predicted to result in the amino acid substitution p.Arg66Trp. This variant was previously reported in individuals with suspected Kallmann syndrome, congenital hypogonadotropic hypogonadism, or CHARGE syndrome; however, this variant has also been reported in apparently unaffected individuals (Hanchate et al. 2012. PubMed ID: 22927827; Cassatella et al. 2018. PubMed ID: 29419413, Table S2; Schulz et al. 2014. PubMed ID: 24728844). In vitro functional analyses indicated that the p.Arg66Trp variant protein impaired secretion of semaphorin-3A, leading authors to speculate that p.Arg66Trp may contribute to disease in a digenic or oligogenic inheritance pattern (Hanchate et al. 2012. PubMed ID: 22927827; Ufartes et al. 2018. PubMed ID: 29432577). This variant is reported in 0.095% of alleles in individuals of South Asian descent in gnomAD. Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at