rs398122943

Variant names:

• chr6-56620289-T-A
• rs398122943
• NM_001723.7:c.3745A>T

Your query was ambiguous. Multiple possible variants found:

• chr6-56620289-T-A
• chr6-56620289-T-C
• chr6-56620289-T-G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001723.7(DST):​c.3745A>T​(p.Arg1249*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DST NM_001723.7 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: 2.03
• Publications: 4 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-56620289-T-A is Pathogenic according to our data. Variant chr6-56620289-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 66013.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DST	NM_001723.7	c.3745A>T	p.Arg1249*	stop_gained	Exon 23 of 24	ENST00000370765.11	NP_001714.1
DST	NM_001374736.1	c.4929+4241A>T		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	c.3745A>T	p.Arg1249*	stop_gained	Exon 23 of 24	1	NM_001723.7	ENSP00000359801.6
DST	ENST00000680361.1	c.4929+4241A>T		intron_variant	Intron 36 of 103		NM_001374736.1	ENSP00000505098.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency Pathogenic:1

Mar 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary sensory and autonomic neuropathy type 6 Uncertain:1

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Uncertain	1.0
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.53	D
PhyloP100		2.0
Vest4		0.73
GERP RS		2.0
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs398122943; hg19: chr6-56485087;