chr5-149010272-G-A

Variant names:

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 (★★). 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

Splicing: ADA: 0.02156

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]

SH3TC2 links:

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
SH3TC2	NM_024577.4 link	c.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
SH3TC2	ENST00000515425.6 link	c.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:

AN:

152210

Hom.:

Cov.:

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:

AN:

251406

Hom.:

AF XY:

0.0000515

AC XY:

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:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

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:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

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.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000494

AC:

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) -

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 -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 28, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

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

- -

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. -

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

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

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. -

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

- -

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. -

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. -

Charcot-Marie-Tooth disease

Pathogenic:2Uncertain:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Benign

0.97

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.44

FATHMM_MKL

Uncertain

0.94

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over