rs141573097

chr6-56618125-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001723.7(DST):c.5909T>C(p.Phe1970Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00436 in 1,614,142 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (35 hom.)
• Consequence: DST NM_001723.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 4.38

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009896845).
• BP6: Variant 6-56618125-A-G is Benign according to our data. Variant chr6-56618125-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 357561.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=2}. Variant chr6-56618125-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00303 (461/152284) while in subpopulation SAS AF= 0.012 (58/4816). AF 95% confidence interval is 0.00956. There are 1 homozygotes in gnomad4. There are 210 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DST	NM_001723.7	c.5909T>C	p.Phe1970Ser	missense_variant	23/24	ENST00000370765.11
DST	NM_001374736.1	c.4930-3641T>C		intron_variant		ENST00000680361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DST	ENST00000370765.11	c.5909T>C	p.Phe1970Ser	missense_variant	23/24	1	NM_001723.7
DST	ENST00000680361.1	c.4930-3641T>C		intron_variant			NM_001374736.1

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 460 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00491

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00434 AC: 1091 AN: 251226 Hom.: 6 AF XY: 0.00471 AC XY: 640 AN XY: 135768

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0107

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.00558

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.00450 AC: 6581 AN: 1461858 Hom.: 35 Cov.: 36 AF XY: 0.00473 AC XY: 3440 AN XY: 727234

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.00337

Gnomad4 NFE exome AF: 0.00460

Gnomad4 OTH exome AF: 0.00373

GnomAD4 genome AF: 0.00303 AC: 461 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.00282 AC XY: 210 AN XY: 74464

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00491

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00448 Hom.: 7

Bravo AF: 0.00244

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00483 AC: 587

Asia WGS AF: 0.00751 AC: 27 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00403

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 25, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2022	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	DST: BP4, BS1, BS2 -

Hereditary sensory and autonomic neuropathy type 6 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.17
Sift	Benign	0.13	T
Sift4G	Benign	0.41	T
Polyphen		0.99	D
Vest4		0.68
MVP		0.55
ClinPred		0.037	T
GERP RS		5.5

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: rs141573097; hg19: chr6-56482923; COSMIC: COSV99761820;