chr5-149028195-C-T

Variant names:

• chr5-149028195-C-T
• rs1554121737
• NM_024577.4:c.1537G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024577.4(SH3TC2):​c.1537G>A​(p.Ala513Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A513S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SH3TC2 NM_024577.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.266
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06414199).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3TC2	NM_024577.4	MANE Select	c.1537G>A	p.Ala513Thr	missense	Exon 11 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.1537G>A	p.Ala513Thr	missense	Exon 11 of 17	ENSP00000423660.1
	SH3TC2	ENST00000512049.5	TSL:1	c.1516G>A	p.Ala506Thr	missense	Exon 11 of 17	ENSP00000421860.1
	SH3TC2	ENST00000323829.9	TSL:1	n.*925G>A		non_coding_transcript_exon	Exon 12 of 18	ENSP00000313025.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 79

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.32
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.20	N
PhyloP100		0.27
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.096
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.053
MutPred		0.35		Gain of phosphorylation at A513 (P = 0.0587)
MVP		0.57
MPC		0.039
ClinPred		0.045	T
GERP RS		2.4
Varity_R		0.026
gMVP		0.075
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1554121737; hg19: chr5-148407758;