5-149004892-T-A
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2
The ENST00000515425.6(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
Genomes: 𝑓 0.0031 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0044 ( 23 hom. )
Consequence
SH3TC2
ENST00000515425.6 missense
ENST00000515425.6 missense
Scores
5
12
2
Clinical Significance
Conservation
PhyloP100: 5.89
Genes affected
SH3TC2 (HGNC:29427): (SH3 domain and tetratricopeptide repeats 2) This gene encodes a protein with two N-terminal Src homology 3 (SH3) domains and 10 tetratricopeptide repeat (TPR) motifs, and is a member of a small gene family. The gene product has been proposed to be an adapter or docking molecule. Mutations in this gene result in autosomal recessive Charcot-Marie-Tooth disease type 4C, a childhood-onset neurodegenerative disease characterized by demyelination of motor and sensory neurons. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.05998248).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00307 (467/152266) while in subpopulation NFE AF= 0.00504 (343/68000). AF 95% confidence interval is 0.0046. There are 0 homozygotes in gnomad4. There are 218 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 23 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SH3TC2 | NM_024577.4 | c.3686A>T | p.Asp1229Val | missense_variant | 17/17 | ENST00000515425.6 | NP_078853.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SH3TC2 | ENST00000515425.6 | c.3686A>T | p.Asp1229Val | missense_variant | 17/17 | 1 | NM_024577.4 | ENSP00000423660 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00308 AC: 468AN: 152152Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00262 AC: 657AN: 251182Hom.: 1 AF XY: 0.00281 AC XY: 381AN XY: 135778
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GnomAD4 exome AF: 0.00442 AC: 6460AN: 1461870Hom.: 23 Cov.: 31 AF XY: 0.00428 AC XY: 3110AN XY: 727240
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GnomAD4 genome AF: 0.00307 AC: 467AN: 152266Hom.: 0 Cov.: 32 AF XY: 0.00293 AC XY: 218AN XY: 74452
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:9
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 22, 2018 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Nov 08, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 10, 2020 | - - |
not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 25, 2020 | This variant is associated with the following publications: (PMID: 21291453, 27884173, 25025039, 27582484, 32376792) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 22, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2024 | SH3TC2: BS2 - |
Charcot-Marie-Tooth disease Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Charcot-Marie-Tooth disease type 4C Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Susceptibility to mononeuropathy of the median nerve, mild Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 13, 2018 | 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
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 22, 2021 | 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
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 16, 2020 | 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
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;M;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;D;.
Vest4
MVP
MPC
0.31
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at