rs1222150652
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024577.4(SH3TC2):βc.3425_3435delβ(p.Tyr1142PhefsTer38) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.0000055 ( 0 hom. )
Consequence
SH3TC2
NM_024577.4 frameshift
NM_024577.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.55
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-149008893-AAGCCTTCTCAT-A is Pathogenic according to our data. Variant chr5-149008893-AAGCCTTCTCAT-A is described in ClinVar as [Pathogenic]. Clinvar id is 543408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SH3TC2 | NM_024577.4 | c.3425_3435del | p.Tyr1142PhefsTer38 | frameshift_variant | 15/17 | ENST00000515425.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SH3TC2 | ENST00000515425.6 | c.3425_3435del | p.Tyr1142PhefsTer38 | frameshift_variant | 15/17 | 1 | NM_024577.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251496Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135922
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461884Hom.: 0 AF XY: 0.00000550 AC XY: 4AN XY: 727242
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease type 4C Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Mar 21, 2023 | The SH3TC2 c.3425_3435del variant is classified as PATHOGENIC (PVS1, PM2, PM3, PS4_supporting) This SH3TC2 c.3425_3435del variant is located in exon 15/17 and is predicted to cause a shift in the reading frame at codon 1142 (PVS1). The variant is rare in population databases (gnomAD allele frequency = 0.00065%; 1 het and 0 hom in 152148 sequenced alleles; highest frequency = 0.0024%, African/African American population) (PM2). This variant has been detected in trans with the pathogenic variant NM_024577.4:c.2860C>T for this recessive condition (PM3). The variant has been reported in dbSNP (rs1222150652) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 543408) (PS4_supporting). It has not been reported in HGMD. - |
Charcot-Marie-Tooth disease type 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 10, 2020 | This variant has not been reported in the literature in individuals with SH3TC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 543408). Loss-of-function variants in SH3TC2 are known to be pathogenic (PMID: 20220177, 27068304). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Tyr1142Phefs*38) in the SH3TC2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). - |
Charcot-Marie-Tooth disease, type I Uncertain:1
Uncertain significance, no assertion criteria provided | research | Genesis Genome Database | Aug 14, 2019 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at