rs115890942

chr6-56624631-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001374736.1(DST):c.4831-3C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,585,620 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (22 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (18 hom.)
• Consequence: DST NM_001374736.1 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.8860
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.72

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 6-56624631-G-T is Benign according to our data. Variant chr6-56624631-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 357591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00952 (1447/152064) while in subpopulation AFR AF= 0.0327 (1358/41494). AF 95% confidence interval is 0.0313. There are 22 homozygotes in gnomad4. There are 659 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DST	NM_001374736.1	c.4831-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000680361.1
DST	NM_001723.7	c.3220-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000370765.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DST	ENST00000370765.11	c.3220-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001723.7
DST	ENST00000680361.1	c.4831-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001374736.1

Frequencies

GnomAD3 genomes AF: 0.00955 AC: 1451 AN: 151946 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00440

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00720

GnomAD3 exomes AF: 0.00225 AC: 562 AN: 249788 Hom.: 10 AF XY: 0.00160 AC XY: 216 AN XY: 135122

Gnomad AFR exome AF: 0.0312

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000797

Gnomad OTH exome AF: 0.000985

GnomAD4 exome AF: 0.000908 AC: 1302 AN: 1433556 Hom.: 18 Cov.: 26 AF XY: 0.000781 AC XY: 558 AN XY: 714898

Gnomad4 AFR exome AF: 0.0323

Gnomad4 AMR exome AF: 0.00166

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000817

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000386

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.00952 AC: 1447 AN: 152064 Hom.: 22 Cov.: 32 AF XY: 0.00886 AC XY: 659 AN XY: 74342

Gnomad4 AFR AF: 0.0327

Gnomad4 AMR AF: 0.00433

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.00274 Hom.: 2

Bravo AF: 0.0109

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DST-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2024

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). -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Hereditary sensory and autonomic neuropathy type 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	15
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Benign	0.64
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs115890942; hg19: chr6-56489429;