rs45472691

Positions:

chr6-56619985-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001723.7(DST):c.4049C>T(p.Thr1350Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,613,928 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 3 hom. )

Consequence

DST
NM_001723.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -1.34

Variant links:

Genes affected

DST (HGNC:1090): (dystonin) This gene encodes a member of the plakin protein family of adhesion junction plaque proteins. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the full-length nature of some variants has not been defined. It has been reported that some isoforms are expressed in neural and muscle tissue, anchoring neural intermediate filaments to the actin cytoskeleton, and some isoforms are expressed in epithelial tissue, anchoring keratin-containing intermediate filaments to hemidesmosomes. Consistent with the expression, mice defective for this gene show skin blistering and neurodegeneration. [provided by RefSeq, Mar 2010]

DST links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005272925).

BP6

Variant 6-56619985-G-A is Benign according to our data. Variant chr6-56619985-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 357581.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr6-56619985-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DST	NM_001723.7 linkuse as main transcript	c.4049C>T	p.Thr1350Met	missense_variant	23/24	ENST00000370765.11	NP_001714.1
DST	NM_001374736.1 linkuse as main transcript	c.4929+4545C>T		intron_variant		ENST00000680361.1	NP_001361665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000370765.11 linkuse as main transcript	c.4049C>T	p.Thr1350Met	missense_variant	23/24	1	NM_001723.7	ENSP00000359801		Q03001-3
DST	ENST00000680361.1 linkuse as main transcript	c.4929+4545C>T		intron_variant			NM_001374736.1	ENSP00000505098

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

195

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00634

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00151

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.00158

AC:

397

AN:

251154

Hom.:

AF XY:

0.00167

AC XY:

227

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00387

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00648

Gnomad NFE exome

AF:

0.00168

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00150

AC:

2192

AN:

1461798

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

1097

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00421

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00641

Gnomad4 NFE exome

AF:

0.00143

Gnomad4 OTH exome

AF:

0.00166

GnomAD4 genome

AF:

0.00129

AC:

196

AN:

152130

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

110

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00634

Gnomad4 NFE

AF:

0.00151

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.00136

Hom.:

Bravo

AF:

0.000858

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00155

AC:

188

EpiCase

AF:

0.00191

EpiControl

AF:

0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	DST: BP4 -

Hereditary sensory and autonomic neuropathy type 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hereditary sensory and autonomic neuropathy type 6;C3809470:Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

DST-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.52

DANN

Benign

0.78

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.34

M_CAP

Benign

0.0025

MetaRNN

Benign

0.0053

MetaSVM

Benign

-0.97

PROVEAN

Benign

-1.0

REVEL

Benign

0.018

Sift

Benign

0.14

Sift4G

Benign

0.099

Polyphen

0.0010

Vest4

0.13

MVP

0.13

ClinPred

0.0037

GERP RS

0.57

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.

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