chr5-149028011-T-C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. 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

Scores

11
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 5.15

Publications

3 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.34103203).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SH3TC2NM_024577.4 linkc.1721A>G p.Asn574Ser missense_variant Exon 11 of 17 ENST00000515425.6 NP_078853.2 Q8TF17-1A0A514TP98

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SH3TC2ENST00000515425.6 linkc.1721A>G p.Asn574Ser missense_variant Exon 11 of 17 1 NM_024577.4 ENSP00000423660.1 Q8TF17-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152220
Hom.:
0
Cov.:
33
show subpopulations
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
GnomAD2 exomes
AF:
0.000108
AC:
27
AN:
250626
AF XY:
0.000118
show subpopulations
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 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
show subpopulations
African (AFR)
AF:
0.000119
AC:
4
AN:
33480
American (AMR)
AF:
0.0000894
AC:
4
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.000174
AC:
15
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53358
Middle Eastern (MID)
AF:
0.00156
AC:
9
AN:
5768
European-Non Finnish (NFE)
AF:
0.000168
AC:
187
AN:
1112012
Other (OTH)
AF:
0.000281
AC:
17
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.494
Heterozygous variant carriers
0
19
38
56
75
94
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152220
Hom.:
0
Cov.:
33
AF XY:
0.0000807
AC XY:
6
AN XY:
74364
show subpopulations
African (AFR)
AF:
0.0000723
AC:
3
AN:
41466
American (AMR)
AF:
0.00
AC:
0
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000735
AC:
5
AN:
68036
Other (OTH)
AF:
0.000957
AC:
2
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.511
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000178
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:6Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Oct 17, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 10, 2023
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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) -

Charcot-Marie-Tooth disease Uncertain:1
-
Molecular Genetics Laboratory, London Health Sciences Centre
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 4C Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
Jul 25, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Susceptibility to mononeuropathy of the median nerve, mild Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
Jan 09, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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;.
PhyloP100
5.2
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
Mutation Taster
=84/16
polymorphism

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

Other links and lift over

dbSNP: rs201256776; hg19: chr5-148407574; API