rs6909714

Positions:

• chr6-56620688-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001723.7(DST):​c.3346C>T​(p.His1116Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 1,613,836 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1116R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (94 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (100 hom.)
• Consequence: DST NM_001723.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.13

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001804322).
• BP6: Variant 6-56620688-G-A is Benign according to our data. Variant chr6-56620688-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 357588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-56620688-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DST	NM_001723.7	c.3346C>T	p.His1116Tyr	missense_variant	23/24	ENST00000370765.11
DST	NM_001374736.1	c.4929+3842C>T		intron_variant		ENST00000680361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DST	ENST00000370765.11	c.3346C>T	p.His1116Tyr	missense_variant	23/24	1	NM_001723.7
DST	ENST00000680361.1	c.4929+3842C>T		intron_variant			NM_001374736.1

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2961 AN: 152118 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.0676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00754

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00546 AC: 1368 AN: 250324 Hom.: 39 AF XY: 0.00383 AC XY: 519 AN XY: 135336

Gnomad AFR exome AF: 0.0691

Gnomad AMR exome AF: 0.00582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00210 AC: 3063 AN: 1461600 Hom.: 100 Cov.: 34 AF XY: 0.00178 AC XY: 1293 AN XY: 727128

Gnomad4 AFR exome AF: 0.0706

Gnomad4 AMR exome AF: 0.00568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000854

Gnomad4 OTH exome AF: 0.00523

GnomAD4 genome AF: 0.0195 AC: 2964 AN: 152236 Hom.: 94 Cov.: 32 AF XY: 0.0186 AC XY: 1382 AN XY: 74422

Gnomad4 AFR AF: 0.0675

Gnomad4 AMR AF: 0.00753

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00389 Hom.: 36

Bravo AF: 0.0229

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0665 AC: 293

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00666 AC: 808

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

- -

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_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	0.055
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Uncertain	0.020	D
Polyphen		0.26	B
Vest4		0.29
MVP		0.30
ClinPred		0.027	T
GERP RS		4.4

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

LitVar

Other links and lift over

dbSNP: rs6909714; hg19: chr6-56485486;