rs1463859150

chr5-149027204-C-Achr5-149027204-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_024577.4(SH3TC2):c.2528G>T(p.Gly843Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G843E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SH3TC2 NM_024577.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 3.36

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851
• PP5: Variant 5-149027204-C-A is Pathogenic according to our data. Variant chr5-149027204-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 476899.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3TC2	NM_024577.4	c.2528G>T	p.Gly843Val	missense_variant	11/17	ENST00000515425.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3TC2	ENST00000515425.6	c.2528G>T	p.Gly843Val	missense_variant	11/17	1	NM_024577.4	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251128 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135694

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461854 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727232

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth disease type 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 16, 2023

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 843 of the SH3TC2 protein (p.Gly843Val). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 25614874, 32376792; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 476899). 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. For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

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Charcot-Marie-Tooth disease type 4C;C3150596:Susceptibility to mononeuropathy of the median nerve, mild Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.99	D;.
Vest4		0.73
MutPred		0.69		Gain of MoRF binding (P = 0.1106);.;
MVP		0.96
MPC		0.28
ClinPred		0.88	D
GERP RS		5.3
Varity_R		0.41
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1463859150; hg19: chr5-148406767;