rs117804174

Variant names:

• chr5-149004744-C-T
• rs117804174
• NM_024577.4:c.3834G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024577.4(SH3TC2):​c.3834G>A​(p.Ala1278Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,613,796 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (26 hom.)
• Consequence: SH3TC2 NM_024577.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.82
• Publications: 2 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), Ambry Genetics, Orphanet
• susceptibility to mononeuropathy of the median nerve, mild

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-149004744-C-T is Benign according to our data. Variant chr5-149004744-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 351895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.82 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00169 (258/152258) while in subpopulation EAS AF = 0.0299 (154/5144). AF 95% confidence interval is 0.0261. There are 3 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024577.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3TC2	NM_024577.4	MANE Select	c.3834G>A	p.Ala1278Ala	synonymous	Exon 17 of 17	NP_078853.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3TC2	ENST00000515425.6	TSL:1 MANE Select	c.3834G>A	p.Ala1278Ala	synonymous	Exon 17 of 17	ENSP00000423660.1	Q8TF17-1
	SH3TC2	ENST00000512049.5	TSL:1	c.3813G>A	p.Ala1271Ala	synonymous	Exon 17 of 17	ENSP00000421860.1	Q8TF17-5
	SH3TC2	ENST00000323829.9	TSL:1	n.*3222G>A		non_coding_transcript_exon	Exon 18 of 18	ENSP00000313025.5	D6RA65

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 258 AN: 152140 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0299

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00260 AC: 651 AN: 250370 AF XY: 0.00246

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0277

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.000961 AC: 1404 AN: 1461538 Hom.: 26 Cov.: 31 AF XY: 0.000982 AC XY: 714 AN XY: 727074

African (AFR) AF: 0.000777 AC: 26 AN: 33472

American (AMR) AF: 0.000112 AC: 5 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0202 AC: 802 AN: 39698

South Asian (SAS) AF: 0.00346 AC: 298 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5556

European-Non Finnish (NFE) AF: 0.0000540 AC: 60 AN: 1111986

Other (OTH) AF: 0.00351 AC: 212 AN: 60356

GnomAD4 genome AF: 0.00169 AC: 258 AN: 152258 Hom.: 3 Cov.: 32 AF XY: 0.00181 AC XY: 135 AN XY: 74442

African (AFR) AF: 0.00168 AC: 70 AN: 41558

American (AMR) AF: 0.000196 AC: 3 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0299 AC: 154 AN: 5144

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.000721 Hom.: 0

Bravo AF: 0.00178

Asia WGS AF: 0.0240 AC: 82 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	Charcot-Marie-Tooth disease type 4C (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	SH3TC2-related disorder (1)
-	-	1	Susceptibility to mononeuropathy of the median nerve, mild (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.065
DANN	Benign	0.33
PhyloP100		-4.8
Mutation Taster		=100/0	polymorphism

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: rs117804174; hg19: chr5-148384307; COSMIC: COSV60463834;