rs55853803

chr5-149008857-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024577.4(SH3TC2):c.3472G>A(p.Val1158Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 1,614,142 control chromosomes in the GnomAD database, including 920 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (56 hom., cov: 32)
  • Exomes 𝑓: 0.033 (864 hom.)
• Consequence: SH3TC2 NM_024577.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.11

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002704382).
• BP6: Variant 5-149008857-C-T is Benign according to our data. Variant chr5-149008857-C-T is described in ClinVar as [Benign]. Clinvar id is 221185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149008857-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0221 (3362/152342) while in subpopulation SAS AF= 0.043 (208/4832). AF 95% confidence interval is 0.0383. There are 56 homozygotes in gnomad4. There are 1649 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3TC2	NM_024577.4	c.3472G>A	p.Val1158Ile	missense_variant	15/17	ENST00000515425.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3TC2	ENST00000515425.6	c.3472G>A	p.Val1158Ile	missense_variant	15/17	1	NM_024577.4	P2

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3361 AN: 152224 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.00540

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.0606

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0428

Gnomad FIN AF: 0.0201

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0316

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0272 AC: 6842 AN: 251490 Hom.: 139 AF XY: 0.0290 AC XY: 3941 AN XY: 135918

Gnomad AFR exome AF: 0.00554

Gnomad AMR exome AF: 0.0143

Gnomad ASJ exome AF: 0.0575

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0481

Gnomad FIN exome AF: 0.0235

Gnomad NFE exome AF: 0.0309

Gnomad OTH exome AF: 0.0287

GnomAD4 exome AF: 0.0326 AC: 47678 AN: 1461800 Hom.: 864 Cov.: 31 AF XY: 0.0330 AC XY: 24010 AN XY: 727206

Gnomad4 AFR exome AF: 0.00606

Gnomad4 AMR exome AF: 0.0145

Gnomad4 ASJ exome AF: 0.0582

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0457

Gnomad4 FIN exome AF: 0.0228

Gnomad4 NFE exome AF: 0.0343

Gnomad4 OTH exome AF: 0.0318

GnomAD4 genome AF: 0.0221 AC: 3362 AN: 152342 Hom.: 56 Cov.: 32 AF XY: 0.0221 AC XY: 1649 AN XY: 74504

Gnomad4 AFR AF: 0.00539

Gnomad4 AMR AF: 0.0188

Gnomad4 ASJ AF: 0.0606

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0430

Gnomad4 FIN AF: 0.0201

Gnomad4 NFE AF: 0.0316

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0306 Hom.: 121

Bravo AF: 0.0206

TwinsUK AF: 0.0316 AC: 117

ALSPAC AF: 0.0358 AC: 138

ESP6500AA AF: 0.00726 AC: 32

ESP6500EA AF: 0.0336 AC: 289

ExAC AF: 0.0271 AC: 3287

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.0318

EpiControl AF: 0.0296

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2020	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Charcot-Marie-Tooth disease type 4C Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Susceptibility to mononeuropathy of the median nerve, mild Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 25, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Charcot-Marie-Tooth disease type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	13
Dann	Benign	0.87
DEOGEN2	Benign	0.071	T;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.66	T;T
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.30	N;N
REVEL	Benign	0.098
Sift	Benign	0.25	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.0020	B;.
Vest4		0.089
MPC		0.035
ClinPred		0.0029	T
GERP RS		1.7
Varity_R		0.026
gMVP		0.077

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: rs55853803; hg19: chr5-148388420;