rs1432794

Positions:

• chr5-149028145-A-C
• chr5-149028145-A-G
• chr5-149028145-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024577.4(SH3TC2):​c.1587T>G​(p.Arg529=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.971 in 1,614,122 control chromosomes in the GnomAD database, including 761,761 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (73132 hom., cov: 34)
  • Exomes 𝑓: 0.97 (688629 hom.)
• Consequence: SH3TC2 NM_024577.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.0560

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 5-149028145-A-C is Benign according to our data. Variant chr5-149028145-A-C is described in ClinVar as [Benign]. Clinvar id is 130298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149028145-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.056 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.986 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3TC2	NM_024577.4	c.1587T>G	p.Arg529=	synonymous_variant	11/17	ENST00000515425.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3TC2	ENST00000515425.6	c.1587T>G	p.Arg529=	synonymous_variant	11/17	1	NM_024577.4	P2

Frequencies

GnomAD3 genomes AF: 0.980 AC: 149124 AN: 152214 Hom.: 73069 Cov.: 34

Gnomad AFR AF: 0.994

Gnomad AMI AF: 0.928

Gnomad AMR AF: 0.985

Gnomad ASJ AF: 0.991

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.990

Gnomad FIN AF: 0.982

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.967

Gnomad OTH AF: 0.982

GnomAD3 exomes AF: 0.979 AC: 246001 AN: 251340 Hom.: 120404 AF XY: 0.978 AC XY: 132887 AN XY: 135878

Gnomad AFR exome AF: 0.995

Gnomad AMR exome AF: 0.989

Gnomad ASJ exome AF: 0.992

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.986

Gnomad FIN exome AF: 0.982

Gnomad NFE exome AF: 0.966

Gnomad OTH exome AF: 0.976

GnomAD4 exome AF: 0.971 AC: 1418820 AN: 1461790 Hom.: 688629 Cov.: 90 AF XY: 0.971 AC XY: 705805 AN XY: 727208

Gnomad4 AFR exome AF: 0.995

Gnomad4 AMR exome AF: 0.988

Gnomad4 ASJ exome AF: 0.992

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.986

Gnomad4 FIN exome AF: 0.981

Gnomad4 NFE exome AF: 0.966

Gnomad4 OTH exome AF: 0.974

GnomAD4 genome AF: 0.980 AC: 149246 AN: 152332 Hom.: 73132 Cov.: 34 AF XY: 0.981 AC XY: 73078 AN XY: 74484

Gnomad4 AFR AF: 0.994

Gnomad4 AMR AF: 0.985

Gnomad4 ASJ AF: 0.991

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.990

Gnomad4 FIN AF: 0.982

Gnomad4 NFE AF: 0.967

Gnomad4 OTH AF: 0.982

Alfa AF: 0.972 Hom.: 39342

Bravo AF: 0.980

Asia WGS AF: 0.995 AC: 3459 AN: 3478

EpiCase AF: 0.967

EpiControl AF: 0.970

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 05, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -

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	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.3
DANN	Benign	0.58

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: rs1432794; hg19: chr5-148407708;