NM_024577.4:c.3686A>T
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2
The NM_024577.4(SH3TC2):c.3686A>T(p.Asp1229Val) variant causes a missense change. The variant allele was found at a frequency of 0.00429 in 1,614,136 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_024577.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SH3TC2 | NM_024577.4 | c.3686A>T | p.Asp1229Val | missense_variant | Exon 17 of 17 | ENST00000515425.6 | NP_078853.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00308 AC: 468AN: 152152Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00262 AC: 657AN: 251182Hom.: 1 AF XY: 0.00281 AC XY: 381AN XY: 135778
GnomAD4 exome AF: 0.00442 AC: 6460AN: 1461870Hom.: 23 Cov.: 31 AF XY: 0.00428 AC XY: 3110AN XY: 727240
GnomAD4 genome AF: 0.00307 AC: 467AN: 152266Hom.: 0 Cov.: 32 AF XY: 0.00293 AC XY: 218AN XY: 74452
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:2
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The c.3686A>T; p.Asp1229Val variant (rs146920285) has been reported in the heterozygous state, in the absence of any other detected pathogenic SH3TC2 variants, in two HMSN I patients (Lassuthova 2011) and one CMT2 patient; however, the variant did not segregate with disease in the CMT family (Hoyer 2014). This variant is listed in the genome Aggregation Database (gnomAD) with a non-Finnish European population frequency of 0.4% (identified on 510 out of 126,418 chromosomes), in the Saudi Human Genome Program with a frequency of 2.6% (identified on 102 out of 3,920 chromosomes; Abouelhoda 2016), and is classified as likely benign/uncertain significance in ClinVar (ID: 188089). Based on the available information, the p.Asp1229Val variant is likely to be benign. -
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not provided Uncertain:1Benign:2
This variant is associated with the following publications: (PMID: 21291453, 27884173, 25025039, 27582484, 32376792) -
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SH3TC2: BS2 -
Charcot-Marie-Tooth disease Uncertain:1Benign:1
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Charcot-Marie-Tooth disease type 4C Uncertain:1Benign:1
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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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Susceptibility to mononeuropathy of the median nerve, mild Uncertain:1
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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Inborn genetic diseases Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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. -
SH3TC2-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Charcot-Marie-Tooth disease type 4 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at