rs55853803

Variant names:

• chr5-149008857-C-T
• rs55853803
• NM_024577.4:c.3472G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000515425.6(SH3TC2):​c.3472G>A​(p.Val1158Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 1,614,142 control chromosomes in the GnomAD database, including 920 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (56 hom., cov: 32)
  • Exomes 𝑓: 0.033 (864 hom.)
• Consequence: SH3TC2 ENST00000515425.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.11
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002704382).
• BP6: Variant 5-149008857-C-T is Benign according to our data. Variant chr5-149008857-C-T is described in ClinVar as Benign. ClinVar VariationId is 221185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0221 (3362/152342) while in subpopulation SAS AF = 0.043 (208/4832). AF 95% confidence interval is 0.0383. There are 56 homozygotes in GnomAd4. There are 1649 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 56 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000515425.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3TC2	NM_024577.4	MANE Select	c.3472G>A	p.Val1158Ile	missense	Exon 15 of 17	NP_078853.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3TC2	ENST00000515425.6	TSL:1 MANE Select	c.3472G>A	p.Val1158Ile	missense	Exon 15 of 17	ENSP00000423660.1
	SH3TC2	ENST00000512049.5	TSL:1	c.3451G>A	p.Val1151Ile	missense	Exon 15 of 17	ENSP00000421860.1
	SH3TC2	ENST00000323829.9	TSL:1	n.*2860G>A		non_coding_transcript_exon	Exon 16 of 18	ENSP00000313025.5

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3361 AN: 152224 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.00540

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.0606

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0428

Gnomad FIN AF: 0.0201

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0316

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0272 AC: 6842 AN: 251490 AF XY: 0.0290

Gnomad AFR exome AF: 0.00554

Gnomad AMR exome AF: 0.0143

Gnomad ASJ exome AF: 0.0575

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0235

Gnomad NFE exome AF: 0.0309

Gnomad OTH exome AF: 0.0287

GnomAD4 exome AF: 0.0326 AC: 47678 AN: 1461800 Hom.: 864 Cov.: 31 AF XY: 0.0330 AC XY: 24010 AN XY: 727206

African (AFR) AF: 0.00606 AC: 203 AN: 33480

American (AMR) AF: 0.0145 AC: 650 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0582 AC: 1522 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0457 AC: 3939 AN: 86254

European-Finnish (FIN) AF: 0.0228 AC: 1218 AN: 53420

Middle Eastern (MID) AF: 0.0218 AC: 124 AN: 5700

European-Non Finnish (NFE) AF: 0.0343 AC: 38100 AN: 1111998

Other (OTH) AF: 0.0318 AC: 1920 AN: 60388

GnomAD4 genome AF: 0.0221 AC: 3362 AN: 152342 Hom.: 56 Cov.: 32 AF XY: 0.0221 AC XY: 1649 AN XY: 74504

African (AFR) AF: 0.00539 AC: 224 AN: 41568

American (AMR) AF: 0.0188 AC: 288 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0606 AC: 210 AN: 3466

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.0430 AC: 208 AN: 4832

European-Finnish (FIN) AF: 0.0201 AC: 214 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0316 AC: 2149 AN: 68038

Other (OTH) AF: 0.0255 AC: 54 AN: 2114

Alfa AF: 0.0293 Hom.: 231

Bravo AF: 0.0206

TwinsUK AF: 0.0316 AC: 117

ALSPAC AF: 0.0358 AC: 138

ESP6500AA AF: 0.00726 AC: 32

ESP6500EA AF: 0.0336 AC: 289

ExAC AF: 0.0271 AC: 3287

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.0318

EpiControl AF: 0.0296

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Charcot-Marie-Tooth disease type 4C (2)
-	-	2	Susceptibility to mononeuropathy of the median nerve, mild (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.87
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.098
Sift	Benign	0.25	T
Sift4G	Benign	0.44	T
Polyphen		0.0020	B
Vest4		0.089
MPC		0.035
ClinPred		0.0029	T
GERP RS		1.7
Varity_R		0.026
gMVP		0.077
Mutation Taster		=98/2	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: rs55853803; hg19: chr5-148388420;