NM_001374736.1:c.4845G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001374736.1(DST):c.4845G>A(p.Arg1615Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,611,390 control chromosomes in the GnomAD database, including 173 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 11 hom., cov: 32)

Exomes 𝑓: 0.013 ( 162 hom. )

Consequence

DST
NM_001374736.1 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.290

Publications

2 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.043).

BP6

Variant 6-56624614-C-T is Benign according to our data. Variant chr6-56624614-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.29 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0104 (1574/152050) while in subpopulation NFE AF = 0.016 (1088/67960). AF 95% confidence interval is 0.0152. There are 11 homozygotes in GnomAd4. There are 728 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DST	NM_001374736.1 link	c.4845G>A	p.Arg1615Arg	synonymous_variant	Exon 36 of 104	ENST00000680361.1	NP_001361665.1
DST	NM_001723.7 link	c.3234G>A	p.Arg1078Arg	synonymous_variant	Exon 22 of 24	ENST00000370765.11	NP_001714.1	Q03001-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000680361.1 link	c.4845G>A	p.Arg1615Arg	synonymous_variant	Exon 36 of 104		NM_001374736.1	ENSP00000505098.1		A0A7P0T890
DST	ENST00000370765.11 link	c.3234G>A	p.Arg1078Arg	synonymous_variant	Exon 22 of 24	1	NM_001723.7	ENSP00000359801.6		Q03001-3

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1574

AN:

151932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00266

Gnomad AMI

AF:

0.0636

Gnomad AMR

AF:

0.0116

Gnomad ASJ

AF:

0.0251

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00208

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0160

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0103

AC:

2583

AN:

250688

AF XY:

0.0102

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.00920

Gnomad ASJ exome

AF:

0.0247

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00177

Gnomad NFE exome

AF:

0.0158

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.0131

AC:

19146

AN:

1459340

Hom.:

162

Cov.:

AF XY:

0.0127

AC XY:

9235

AN XY:

726166

show subpopulations

African (AFR)

AF:

0.00233

AC:

AN:

33428

American (AMR)

AF:

0.00946

AC:

423

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0223

AC:

582

AN:

26108

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39666

South Asian (SAS)

AF:

0.00208

AC:

179

AN:

86202

European-Finnish (FIN)

AF:

0.00250

AC:

133

AN:

53168

Middle Eastern (MID)

AF:

0.00469

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0153

AC:

16950

AN:

1109984

Other (OTH)

AF:

0.0128

AC:

772

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

855

1710

2564

3419

4274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

614

1228

1842

2456

3070

<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:

0.0104

AC:

1574

AN:

152050

Hom.:

Cov.:

AF XY:

0.00979

AC XY:

728

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.00265

AC:

110

AN:

41510

American (AMR)

AF:

0.0115

AC:

175

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.0251

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00208

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0160

AC:

1088

AN:

67960

Other (OTH)

AF:

0.0114

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

160

240

320

400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0151

Hom.:

Bravo

AF:

0.0111

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0166

EpiControl

AF:

0.0178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 08, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

8.0

(source)

DANN

Benign

0.80

PhyloP100

-0.29

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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