rs1025476

Variant names:

• chr5-149010200-G-A
• rs1025476
• NM_024577.4:c.3327+70C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024577.4(SH3TC2):​c.3327+70C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 1,610,164 control chromosomes in the GnomAD database, including 129,724 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (12796 hom., cov: 32)
  • Exomes 𝑓: 0.40 (116928 hom.)
• Consequence: SH3TC2 NM_024577.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.35
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive hereditary demyelinating motor and sensory neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 4C

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• susceptibility to mononeuropathy of the median nerve, mild

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 5-149010200-G-A is Benign according to our data. Variant chr5-149010200-G-A is described in ClinVar as Benign. ClinVar VariationId is 673389.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3TC2	NM_024577.4	c.3327+70C>T		intron_variant	Intron 14 of 16	ENST00000515425.6	NP_078853.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3TC2	ENST00000515425.6	c.3327+70C>T		intron_variant	Intron 14 of 16	1	NM_024577.4	ENSP00000423660.1

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61787 AN: 151906 Hom.: 12790 Cov.: 32

Gnomad AFR AF: 0.432

Gnomad AMI AF: 0.476

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.482

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.397

GnomAD4 exome AF: 0.398 AC: 579652 AN: 1458140 Hom.: 116928 AF XY: 0.400 AC XY: 290405 AN XY: 725492

African (AFR) AF: 0.436 AC: 14548 AN: 33400

American (AMR) AF: 0.282 AC: 12592 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 11597 AN: 26102

East Asian (EAS) AF: 0.281 AC: 11162 AN: 39662

South Asian (SAS) AF: 0.466 AC: 40142 AN: 86090

European-Finnish (FIN) AF: 0.474 AC: 25272 AN: 53326

Middle Eastern (MID) AF: 0.446 AC: 2233 AN: 5008

European-Non Finnish (NFE) AF: 0.395 AC: 437923 AN: 1109650

Other (OTH) AF: 0.402 AC: 24183 AN: 60218

GnomAD4 genome AF: 0.407 AC: 61825 AN: 152024 Hom.: 12796 Cov.: 32 AF XY: 0.411 AC XY: 30567 AN XY: 74306

African (AFR) AF: 0.431 AC: 17880 AN: 41438

American (AMR) AF: 0.327 AC: 5002 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1566 AN: 3468

East Asian (EAS) AF: 0.270 AC: 1402 AN: 5184

South Asian (SAS) AF: 0.467 AC: 2251 AN: 4816

European-Finnish (FIN) AF: 0.482 AC: 5084 AN: 10552

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.401 AC: 27249 AN: 67972

Other (OTH) AF: 0.399 AC: 843 AN: 2112

Alfa AF: 0.398 Hom.: 33858

Bravo AF: 0.392

Asia WGS AF: 0.349 AC: 1214 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.0050
DANN	Benign	0.53
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1025476; hg19: chr5-148389763; COSMIC: COSV60464084; COSMIC: COSV60464084;