chr5-149028330-C-A

Position:

chr5-149028330-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024577.4(SH3TC2):c.1402G>T(p.Ala468Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,613,826 control chromosomes in the GnomAD database, including 36,254 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A468F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.22 ( 4316 hom., cov: 32)

Exomes 𝑓: 0.20 ( 31938 hom. )

Consequence

SH3TC2
NM_024577.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.01

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043907464).

BP6

Variant 5-149028330-C-A is Benign according to our data. Variant chr5-149028330-C-A is described in ClinVar as [Benign]. Clinvar id is 130297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149028330-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3TC2	NM_024577.4 linkuse as main transcript	c.1402G>T	p.Ala468Ser	missense_variant	11/17	ENST00000515425.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3TC2	ENST00000515425.6 linkuse as main transcript	c.1402G>T	p.Ala468Ser	missense_variant	11/17	1	NM_024577.4	P2	Q8TF17-1

Frequencies

GnomAD3 genomes

AF:

0.225

AC:

34207

AN:

152012

Hom.:

4313

Cov.:

show subpopulations

Gnomad AFR

AF:

0.309

Gnomad AMI

AF:

0.229

Gnomad AMR

AF:

0.159

Gnomad ASJ

AF:

0.248

Gnomad EAS

AF:

0.0266

Gnomad SAS

AF:

0.238

Gnomad FIN

AF:

0.184

Gnomad MID

AF:

0.236

Gnomad NFE

AF:

0.208

Gnomad OTH

AF:

0.228

GnomAD3 exomes

AF:

0.194

AC:

48653

AN:

251050

Hom.:

5439

AF XY:

0.200

AC XY:

27093

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.308

Gnomad AMR exome

AF:

0.114

Gnomad ASJ exome

AF:

0.247

Gnomad EAS exome

AF:

0.0245

Gnomad SAS exome

AF:

0.250

Gnomad FIN exome

AF:

0.184

Gnomad NFE exome

AF:

0.210

Gnomad OTH exome

AF:

0.206

GnomAD4 exome

AF:

0.204

AC:

298174

AN:

1461696

Hom.:

31938

Cov.:

AF XY:

0.206

AC XY:

149861

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.312

Gnomad4 AMR exome

AF:

0.120

Gnomad4 ASJ exome

AF:

0.243

Gnomad4 EAS exome

AF:

0.0374

Gnomad4 SAS exome

AF:

0.249

Gnomad4 FIN exome

AF:

0.179

Gnomad4 NFE exome

AF:

0.206

Gnomad4 OTH exome

AF:

0.204

GnomAD4 genome

AF:

0.225

AC:

34222

AN:

152130

Hom.:

4316

Cov.:

AF XY:

0.224

AC XY:

16642

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.309

Gnomad4 AMR

AF:

0.159

Gnomad4 ASJ

AF:

0.248

Gnomad4 EAS

AF:

0.0265

Gnomad4 SAS

AF:

0.237

Gnomad4 FIN

AF:

0.184

Gnomad4 NFE

AF:

0.208

Gnomad4 OTH

AF:

0.232

Alfa

AF:

0.203

Hom.:

7406

Bravo

AF:

0.222

TwinsUK

AF:

0.216

AC:

800

ALSPAC

AF:

0.209

AC:

807

ESP6500AA

AF:

0.306

AC:

1347

ESP6500EA

AF:

0.204

AC:

1752

ExAC

AF:

0.201

AC:

24405

EpiCase

AF:

0.218

EpiControl

AF:

0.222

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

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 13, 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 13, 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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

9.0

DANN

Benign

0.85

DEOGEN2

Benign

0.051

T;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.79

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.47

T;T

MetaRNN

Benign

0.0044

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;.

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.23

PROVEAN

Benign

0.56

N;N

REVEL

Benign

0.17

Sift

Benign

0.69

T;T

Sift4G

Benign

0.34

T;T

Polyphen

0.88

P;.

Vest4

0.11

MPC

0.045

ClinPred

0.0098

GERP RS

0.80

Varity_R

0.034

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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