rs45487998

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001723.7(DST):c.5153A>C(p.Lys1718Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,614,168 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 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 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 13 hom. )

Consequence

DST
NM_001723.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.107

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

hereditary sensory and autonomic neuropathy type 6
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

DST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00559631).

BP6

Variant 6-56618881-T-G is Benign according to our data. Variant chr6-56618881-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 357566.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00238 (363/152314) while in subpopulation NFE AF = 0.00388 (264/68032). AF 95% confidence interval is 0.0035. There are 0 homozygotes in GnomAd4. There are 155 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DST	NM_001723.7 link	c.5153A>C	p.Lys1718Thr	missense_variant	Exon 23 of 24	ENST00000370765.11	NP_001714.1	Q03001-3
DST	NM_001374736.1 link	c.4930-4397A>C		intron_variant	Intron 36 of 103	ENST00000680361.1	NP_001361665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000370765.11 link	c.5153A>C	p.Lys1718Thr	missense_variant	Exon 23 of 24	1	NM_001723.7	ENSP00000359801.6		Q03001-3
DST	ENST00000680361.1 link	c.4930-4397A>C		intron_variant	Intron 36 of 103		NM_001374736.1	ENSP00000505098.1		A0A7P0T890

Frequencies

GnomAD3 genomes

AF:

0.00240

AC:

365

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00388

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00266

AC:

666

AN:

250676

AF XY:

0.00284

show subpopulations

Gnomad AFR exome

AF:

0.000741

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000971

Gnomad NFE exome

AF:

0.00392

Gnomad OTH exome

AF:

0.00360

GnomAD4 exome

AF:

0.00347

AC:

5066

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00348

AC XY:

2534

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.000717

AC:

AN:

33480

American (AMR)

AF:

0.00279

AC:

125

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00208

AC:

179

AN:

86256

European-Finnish (FIN)

AF:

0.00107

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00404

AC:

4494

AN:

1112004

Other (OTH)

AF:

0.00285

AC:

172

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

286

571

857

1142

1428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

158

316

474

632

790

<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:

0.00238

AC:

363

AN:

152314

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

155

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000962

AC:

AN:

41566

American (AMR)

AF:

0.00242

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00145

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00388

AC:

264

AN:

68032

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00347

Hom.:

Bravo

AF:

0.00261

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00263

AC:

319

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00556

EpiControl

AF:

0.00539

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary sensory and autonomic neuropathy type 6

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 18, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DST c.5153A>C (p.Lys1718Thr) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 1607194 control chromosomes, predominantly at a frequency of 0.004 within the Non-Finnish European subpopulation in the gnomAD database, including 10 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in DST causing Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency phenotype (0.0011). To our knowledge, no occurrence of c.5153A>C in individuals affected with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 357566). Based on the evidence outlined above, the variant was classified as likely benign. -

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

Benign:1

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jun 21, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DST: BP4, BS1 -

DST-related disorder

Benign:1

May 11, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Benign

9.0

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.73

M_CAP

Benign

0.0044

MetaRNN

Benign

0.0056

MetaSVM

Benign

-1.0

PhyloP100

0.11

PROVEAN

Benign

-1.3

REVEL

Benign

0.048

Sift

Uncertain

0.018

Sift4G

Benign

0.068

Polyphen

0.84

Vest4

0.30

MVP

0.30

ClinPred

0.0057

GERP RS

1.5

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over