NM_001723.7:c.3724T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_001723.7(DST):c.3724T>C(p.Leu1242Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,614,070 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 4 hom. )

Consequence

DST
NM_001723.7 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.157

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: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 6-56620310-A-G is Benign according to our data. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56620310-A-G is described in CliVar as Benign. Clinvar id is 474523.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.157 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000394 (60/152182) while in subpopulation EAS AF = 0.00966 (50/5176). AF 95% confidence interval is 0.00753. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DST	NM_001723.7 link	c.3724T>C	p.Leu1242Leu	synonymous_variant	Exon 23 of 24	ENST00000370765.11	NP_001714.1	Q03001-3
DST	NM_001374736.1 link	c.4929+4220T>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.3724T>C	p.Leu1242Leu	synonymous_variant	Exon 23 of 24	1	NM_001723.7	ENSP00000359801.6		Q03001-3
DST	ENST00000680361.1 link	c.4929+4220T>C		intron_variant	Intron 36 of 103		NM_001374736.1	ENSP00000505098.1		A0A7P0T890

Frequencies

GnomAD3 genomes

AF:

0.000395

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00964

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000842

AC:

211

AN:

250728

AF XY:

0.000745

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0108

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000194

AC:

284

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

122

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00443

AC:

176

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1112012

Other (OTH)

AF:

0.00137

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.000394

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41532

American (AMR)

AF:

0.000131

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00966

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67998

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000195

Hom.:

Bravo

AF:

0.000491

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DST-related disorder

Benign:1

Mar 08, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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_noAF

Benign

-0.66

CADD

Benign

0.65

(source)

DANN

Benign

0.41

PhyloP100

-0.16

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