rs147800229

chr5-149007085-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3 BP6_Very_Strong BS1

The NM_024577.4(SH3TC2):c.3479-8A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,613,900 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: SH3TC2 NM_024577.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9971
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.248

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 -11 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 5-149007085-T-C is Benign according to our data. Variant chr5-149007085-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 476907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00208 (316/152238) while in subpopulation AFR AF= 0.00737 (306/41532). AF 95% confidence interval is 0.00669. There are 1 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3TC2	NM_024577.4	c.3479-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000515425.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3TC2	ENST00000515425.6	c.3479-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_024577.4	P2

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 316 AN: 152120 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00739

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000625 AC: 157 AN: 251050 Hom.: 0 AF XY: 0.000486 AC XY: 66 AN XY: 135692

Gnomad AFR exome AF: 0.00898

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000237 AC: 346 AN: 1461662 Hom.: 1 Cov.: 31 AF XY: 0.000213 AC XY: 155 AN XY: 727176

Gnomad4 AFR exome AF: 0.00813

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.00208 AC: 316 AN: 152238 Hom.: 1 Cov.: 32 AF XY: 0.00207 AC XY: 154 AN XY: 74436

Gnomad4 AFR AF: 0.00737

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00149 Hom.: 1

Bravo AF: 0.00253

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 11, 2019	- -

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

SH3TC2-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Charcot-Marie-Tooth disease type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	20
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.52		Position offset: 7
DS_AL_spliceai		0.76		Position offset: -8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs147800229; hg19: chr5-148386648;