rs763331671

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

The NM_024577.4(SH3TC2):​c.2989C>T​(p.Arg997Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

SH3TC2
NM_024577.4 missense

Scores

2
13
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.15
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 5-149026636-G-A is Benign according to our data. Variant chr5-149026636-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 578843.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SH3TC2NM_024577.4 linkuse as main transcriptc.2989C>T p.Arg997Trp missense_variant 12/17 ENST00000515425.6 NP_078853.2 Q8TF17-1A0A514TP98

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SH3TC2ENST00000515425.6 linkuse as main transcriptc.2989C>T p.Arg997Trp missense_variant 12/171 NM_024577.4 ENSP00000423660.1 Q8TF17-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152124
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000517
AC:
13
AN:
251470
Hom.:
0
AF XY:
0.0000441
AC XY:
6
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461890
Hom.:
0
Cov.:
30
AF XY:
0.0000151
AC XY:
11
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000277
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000719
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152124
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74310
show subpopulations
Gnomad4 AFR
AF:
0.0000966
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 10, 2024Variant summary: SH3TC2 c.2989C>T (p.Arg997Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251470 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SH3TC2 causing Charcot-Marie Disease Type 4C, allowing no conclusion about variant significance. c.2989C>T has been reported in the literature in an individual affected with Charcot-Marie Disease, however the variant co-occurred with a pathogenic variant (PMP22 c.215C>T, p.Ser72Leu), providing supporting evidence for a benign role (Choi_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22730194). ClinVar contains an entry for this variant (Variation ID: 578843). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Charcot-Marie-Tooth disease type 4 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 13, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.090
T
BayesDel_noAF
Uncertain
-0.020
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.56
D;.
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Uncertain
0.69
D;D
MetaSVM
Uncertain
0.0020
D
MutationAssessor
Benign
1.9
L;.
PrimateAI
Uncertain
0.49
T
PROVEAN
Pathogenic
-5.0
D;D
REVEL
Uncertain
0.59
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
D;.
Vest4
0.63
MVP
0.84
MPC
0.28
ClinPred
0.73
D
GERP RS
3.5
Varity_R
0.45
gMVP
0.50

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs763331671; hg19: chr5-148406199; API