Variant rs184593694 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024577.4(SH3TC2):c.385+3A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000459 in 1,611,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

SH3TC2
NM_024577.4 splice_region, intron

Scores

Splicing: ADA: 0.9992

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 6.42

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 links:

SH3TC2 (HGNC:):

SH3TC2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3TC2	NM_024577.4 linkuse as main transcript	c.385+3A>G		splice_region_variant, intron_variant		ENST00000515425.6	NP_078853.2	Q8TF17-1A0A514TP98

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3TC2	ENST00000515425.6 linkuse as main transcript	c.385+3A>G		splice_region_variant, intron_variant		1	NM_024577.4	ENSP00000423660.1		Q8TF17-1

Frequencies

GnomAD3 genomes

AF:

0.000232

AC:

AN:

151154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000865

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:

0.0000798

AC:

AN:

250764

Hom.:

AF XY:

0.0000664

AC XY:

AN XY:

135572

show subpopulations

Gnomad AFR exome

AF:

0.000946

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1459776

Hom.:

Cov.:

AF XY:

0.0000262

AC XY:

AN XY:

726340

show subpopulations

Gnomad4 AFR exome

AF:

0.000778

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.000231

AC:

AN:

151268

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

AN XY:

74034

show subpopulations

Gnomad4 AFR

AF:

0.000862

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:

0.000330

Hom.:

Bravo

AF:

0.000204

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 26, 2024

- -

SH3TC2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 23, 2024

The SH3TC2 c.385+3A>G variant is predicted to interfere with splicing. This variant was reported in the homozygous state as a variant of uncertain significance in an individual with Charcot-Marie-Tooth disease (Supp. Table 2 Volodarsky et al 2021. PubMed ID: 32376792). This variant is reported in 0.094% of alleles in individuals of African descent in gnomAD and is likely too common to be a primary cause of autosomal dominant SH3TC2-related disorders. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Charcot-Marie-Tooth disease type 4C;C3150596:Susceptibility to mononeuropathy of the median nerve, mild

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 11, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Skane University Hospital Lund

Apr 04, 2023

- -

Tip-toe gait

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

May 05, 2023

Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

Charcot-Marie-Tooth disease type 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

This sequence change falls in intron 4 of the SH3TC2 gene. It does not directly change the encoded amino acid sequence of the SH3TC2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs184593694, gnomAD 0.09%). This variant has been observed in individual(s) with SH3TC2-related conditions (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 568124). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.28

Position offset: 3

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over