rs772013916

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PVS1BS1_SupportingBS2

The NM_001723.7(DST):c.6047_6048dupAG(p.Ile2017fs) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000708 in 1,612,024 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 2 hom. )

Consequence

DST
NM_001723.7 frameshift, splice_region

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.34

Publications

0 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: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000736 (1074/1459806) while in subpopulation SAS AF = 0.00152 (131/86214). AF 95% confidence interval is 0.00131. There are 2 homozygotes in GnomAdExome4. There are 522 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DST	NM_001723.7 link	c.6047_6048dupAG	p.Ile2017fs	frameshift_variant, splice_region_variant	Exon 23 of 24	ENST00000370765.11	NP_001714.1	Q03001-3
DST	NM_001374736.1 link	c.4930-3503_4930-3502dupAG		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.6047_6048dupAG	p.Ile2017fs	frameshift_variant, splice_region_variant	Exon 23 of 24	1	NM_001723.7	ENSP00000359801.6		Q03001-3
DST	ENST00000680361.1 link	c.4930-3503_4930-3502dupAG		intron_variant	Intron 36 of 103		NM_001374736.1	ENSP00000505098.1		A0A7P0T890

Frequencies

GnomAD3 genomes

AF:

0.000440

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000497

AC:

125

AN:

251270

AF XY:

0.000560

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000678

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000736

AC:

1074

AN:

1459806

Hom.:

Cov.:

AF XY:

0.000719

AC XY:

522

AN XY:

726416

show subpopulations

African (AFR)

AF:

0.0000898

AC:

AN:

33426

American (AMR)

AF:

0.000112

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26116

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39692

South Asian (SAS)

AF:

0.00152

AC:

131

AN:

86214

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000806

AC:

895

AN:

1110128

Other (OTH)

AF:

0.000497

AC:

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

100

151

201

251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000440

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41546

American (AMR)

AF:

0.000262

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00104

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000794

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000772

Hom.:

Bravo

AF:

0.000476

EpiCase

AF:

0.000763

EpiControl

AF:

0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1

Jan 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (Splice site) in the DST gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 633 amino acid(s) of the DST protein. This variant is present in population databases (rs772013916, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DST-related conditions. ClinVar contains an entry for this variant (Variation ID: 474536). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

not provided

Uncertain:1

Apr 15, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 633 amino acids are replaced with 1 different amino acids, and other similar variants have been reported in HGMD; Has not been previously published as pathogenic or benign to our knowledge -

DST-related disorder

Uncertain:1

Dec 19, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DST c.6047_6048dupAG variant is predicted to result in a frameshift and premature protein termination (p.Ile2017Argfs*2). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.14% of alleles in individuals of South Asian descent in gnomAD (including one homozygous record), which is likely too common for an undocumented disease-causing variant. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.3

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs772013916

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