chr5-149010272-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024577.4(SH3TC2):​c.3325C>T​(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

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

SH3TC2
NM_024577.4 stop_gained, splice_region

Scores

2
1
4
Splicing: ADA: 0.02156
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18U:1O:1

Conservation

PhyloP100: 1.47
Variant links:
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]

Genome browser will be placed here

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 5-149010272-G-A is Pathogenic according to our data. Variant chr5-149010272-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149010272-G-A is described in Lovd as [Pathogenic]. Variant chr5-149010272-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SH3TC2NM_024577.4 linkc.3325C>T p.Arg1109* stop_gained, splice_region_variant Exon 14 of 17 ENST00000515425.6 NP_078853.2 Q8TF17-1A0A514TP98

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SH3TC2ENST00000515425.6 linkc.3325C>T p.Arg1109* stop_gained, splice_region_variant Exon 14 of 17 1 NM_024577.4 ENSP00000423660.1 Q8TF17-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152210
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251406
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.0000993
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000301
AC:
44
AN:
1461850
Hom.:
0
Cov.:
33
AF XY:
0.0000426
AC XY:
31
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000765
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000220
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152328
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000491
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:18Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:8
Jan 18, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

May 27, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 01, 2016
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 28, 2022
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 03, 2024
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Aug 04, 2022
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP1, PM2, PM3, PS4_moderate, PVS1 -

-
Clinical Genetics, Academic Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 4C Pathogenic:6Other:1
Apr 01, 2007
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jun 23, 2023
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 Romberg’s 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. -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Jun 22, 2023
Neuberg Centre For Genomic Medicine, NCGM
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Feb 22, 2022
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1, PM2, PM3, PP5 -

Feb 23, 2023
3billion, Medical Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Oct 10, 2018
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
-
Inherited Neuropathy Consortium
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: provider interpretation

- -

Aug 14, 2019
Genesis Genome Database
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

-
Molecular Genetics Laboratory, London Health Sciences Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 4C;C3150596:Susceptibility to mononeuropathy of the median nerve, mild Pathogenic:1
Apr 09, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 4 Pathogenic:1
Oct 18, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
36
DANN
Benign
0.97
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.44
FATHMM_MKL
Uncertain
0.94
D
Vest4
0.94
GERP RS
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.022
dbscSNV1_RF
Benign
0.33
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80338934; hg19: chr5-148389835; COSMIC: COSV60463545; COSMIC: COSV60463545; API