rs375889300

Variant names:

• chr6-56627275-C-A
• rs375889300
• NM_001374736.1:c.4651G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-56627275-C-A
• chr6-56627275-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001374736.1(DST):​c.4651G>T​(p.Glu1551*) variant causes a stop gained change involving the alteration of a 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DST NM_001374736.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91
• Publications: 1 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 12 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 6-56627275-C-A is Pathogenic according to our data. Variant chr6-56627275-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 665283.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DST	NM_001374736.1	c.4651G>T	p.Glu1551*	stop_gained	Exon 34 of 104	ENST00000680361.1	NP_001361665.1
DST	NM_001723.7	c.3040G>T	p.Glu1014*	stop_gained	Exon 20 of 24	ENST00000370765.11	NP_001714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000680361.1	c.4651G>T	p.Glu1551*	stop_gained	Exon 34 of 104		NM_001374736.1	ENSP00000505098.1
DST	ENST00000370765.11	c.3040G>T	p.Glu1014*	stop_gained	Exon 20 of 24	1	NM_001723.7	ENSP00000359801.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary sensory and autonomic neuropathy type 6;C3809470:Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency Pathogenic:1

Dec 25, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Loss-of-function variants in DST are known to be pathogenic (PMID: 25059916). This variant has not been reported in the literature in individuals with DST-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu1014*) in the DST gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	42
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.9
Vest4		0.87
GERP RS		5.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs375889300; hg19: chr6-56492073;