5-149010272-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024577.4(SH3TC2):βc.3325C>Tβ(p.Arg1109*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_024577.4 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SH3TC2 | NM_024577.4 | c.3325C>T | p.Arg1109* | stop_gained, splice_region_variant | Exon 14 of 17 | ENST00000515425.6 | NP_078853.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251406Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135876
GnomAD4 exome AF: 0.0000301 AC: 44AN: 1461850Hom.: 0 Cov.: 33 AF XY: 0.0000426 AC XY: 31AN XY: 727224
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152328Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74484
ClinVar
Submissions by phenotype
not provided Pathogenic:8
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29321516, 30373780, 30653784, 17470135, 22978647, 25525159, 20301514, 16326826, 31634715, 31127727, 31589614, 32376792) -
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This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant associates with disease in multiple families. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
PP1, PM2, PM3, PS4_moderate, PVS1 -
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Charcot-Marie-Tooth disease type 4C Pathogenic:6Other:1
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The homozygous pathogenic variant c.3325C>T (p.Arg1109*) has been identified in a proband with phenotypic features of motor delay, frequent falls, difficulty in climbing stairs, asymmetry of face, proximal muscle weakness of lower limbs, positive Rombergβs sign. This variant is identified in exon 14 of SH3TC2 gene. Loss of function is a reported mechanism in SH3TC2 with 104 null pathogenic variants. This variant is predicted to cause NMD. Hence, the ACMG criteria of PVS1_very strong is met. The variant is present in 0.0042% in gnomAD (aggregated) database (PM2_moderate). It has been previously reported (PP5_supporting) PMID 16806930. -
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The observed stop gained c.3325C>T(p.Arg1109Ter) variant in SH3TC2 gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with Charcot-Marie-tooth disease type 4 (CMT4D) (Moosavi et al., 2020). This variant is reported with the allele frequency of 0.004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain significance / Likely Pathogenic / Pathogenic (multiple submissions). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss of function variants have been previously reported to be disease causing (Vijay et al., 2016). Computational evidence (MutationTaster - Disease causing automatic) predicts damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. -
PVS1, PM2, PM3, PP5 -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. It has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (PMID: 16326826). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
The p.Arg1109X variant in SH3TC2 has been reported in more than 10 individuals w ith Charcot-Marie-Tooth disease type 4C and segregated with disease in 16 affect ed family members from families (Gooding 2005, Colomer 2006, Claramunt 2007, Sev illa 2013, Piscosquito 2016, Lupo 2016, Khadilkar 2017, Yuan 2018). It has been shown to be a founder mutation in the Spanish Gypsy population (Gooding 2005, Cl aramunt 2007). It has also been identified in 0.02% (7/30778) of South Asian chr omosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant lea ds to a premature termination codon at position 1109, which is predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Charcot-Marie-Tooth disease ty pe 4C based on case observations, segregation studies, and predicted impact on p rotein. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PP1_Strong. -
Charcot-Marie-Tooth disease Pathogenic:2Uncertain:1
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Charcot-Marie-Tooth disease type 4C;C3150596:Susceptibility to mononeuropathy of the median nerve, mild Pathogenic:1
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Charcot-Marie-Tooth disease type 4 Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg1109*) in the SH3TC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SH3TC2 are known to be pathogenic (PMID: 20220177, 27068304). This variant is present in population databases (rs80338934, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Charcot-Marie-Tooth disease, type 4C (CMT4C) (PMID: 16326826, 17470135, 22978647, 26752306, 27231023). It is commonly reported in individuals of Spanish ancestry (PMID: 16326826, 17470135). ClinVar contains an entry for this variant (Variation ID: 2483). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at