Genetic Variant SH3TC2:p.Arg1109Gly (chr5-149010272-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_024577.4(SH3TC2):c.3325C>G(p.Arg1109Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R1109P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SH3TC2
NM_024577.4 missense, splice_region

Scores

Splicing: ADA: 0.0001714

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.47

Publications

0 publications found

Variant links:

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

SH3TC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.833

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.3325C>G	p.Arg1109Gly	missense splice_region	Exon 14 of 17	NP_078853.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SH3TC2	ENST00000515425.6	TSL:1 MANE Select	c.3325C>G	p.Arg1109Gly	missense splice_region	Exon 14 of 17	ENSP00000423660.1
SH3TC2	ENST00000512049.5	TSL:1	c.3304C>G	p.Arg1102Gly	missense splice_region	Exon 14 of 17	ENSP00000421860.1
SH3TC2	ENST00000323829.9	TSL:1	n.*2713C>G		splice_region non_coding_transcript_exon	Exon 15 of 18	ENSP00000313025.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.53

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.25

MutationAssessor

Uncertain

2.8

PhyloP100

1.5

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-6.2

REVEL

Uncertain

0.57

Sift

Uncertain

0.020

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.84

MutPred

0.47

Loss of MoRF binding (P = 0.0156)

MVP

0.83

MPC

0.31

ClinPred

1.0

GERP RS

1.7

Varity_R

0.55

gMVP

0.56

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00017

dbscSNV1_RF

Benign

0.086

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over