rs1554121765

Positions:

• chr5-149028372-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024577.4(SH3TC2):​c.1360A>G​(p.Met454Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SH3TC2 NM_024577.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.648

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.101542026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3TC2	NM_024577.4	c.1360A>G	p.Met454Val	missense_variant	11/17	ENST00000515425.6	NP_078853.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3TC2	ENST00000515425.6	c.1360A>G	p.Met454Val	missense_variant	11/17	1	NM_024577.4	ENSP00000423660.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461838 Hom.: 0 Cov.: 79 AF XY: 0.00000550 AC XY: 4 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 21, 2017

- -

Charcot-Marie-Tooth disease type 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 454 of the SH3TC2 protein (p.Met454Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SH3TC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 448365). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SH3TC2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.7
DANN	Benign	0.46
DEOGEN2	Benign	0.070	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.92
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.98	L;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.63	N;N
REVEL	Benign	0.16
Sift	Benign	0.31	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.078
MutPred		0.21		Loss of phosphorylation at S457 (P = 0.1603);.;
MVP		0.43
MPC		0.040
ClinPred		0.44	T
GERP RS		-2.3
Varity_R		0.068
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs1554121765; hg19: chr5-148407935; COSMIC: COSV105905297; COSMIC: COSV105905297;