rs201256776

chr5-149028011-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024577.4(SH3TC2):c.1721A>G(p.Asn574Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000153 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: SH3TC2 NM_024577.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 5.15

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34103203).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3TC2	NM_024577.4	c.1721A>G	p.Asn574Ser	missense_variant	11/17	ENST00000515425.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3TC2	ENST00000515425.6	c.1721A>G	p.Asn574Ser	missense_variant	11/17	1	NM_024577.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000108 AC: 27 AN: 250626 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135484

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000161 AC: 236 AN: 1461830 Hom.: 0 Cov.: 33 AF XY: 0.000162 AC XY: 118 AN XY: 727208

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000168

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74364

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000186 Hom.: 0

Bravo AF: 0.0000982

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Charcot-Marie-Tooth disease type 4C Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

The c.1721A>G (p.N574S) alteration is located in exon 11 (coding exon 11) of the SH3TC2 gene. This alteration results from a A to G substitution at nucleotide position 1721, causing the asparagine (N) at amino acid position 574 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 10, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported previously as a variant of uncertain significance in a patient with a suspected diagnosis of Charcot-Marie-Tooth disease; however, clinical and segregation information was not provided (Volodarsky et al., 2021); Previously reported as a variant of uncertain significance in an individual with PHARC syndrome who also homozygous for a nonsense variant in another gene associated with this syndrome (Thimm et al., 2020); This variant is associated with the following publications: (PMID: 32376792, 32077159, 25614874) -

Susceptibility to mononeuropathy of the median nerve, mild Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Charcot-Marie-Tooth disease type 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	-0.064	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	0.94	D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.43
Sift	Benign	0.044	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		1.0	D;.
Vest4		0.38
MVP		0.87
MPC		0.050
ClinPred		0.20	T
GERP RS		3.6
Varity_R		0.14
gMVP		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs201256776; hg19: chr5-148407574;