rs141573097

Variant names:

• chr6-56618125-A-G
• rs141573097
• NM_001723.7:c.5909T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-56618125-A-G
• chr6-56618125-A-C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 357561.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 35 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001723.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	NM_001723.7	MANE Plus Clinical	c.5909T>C	p.Phe1970Ser	missense	Exon 23 of 24	NP_001714.1	Q03001-3
	DST	NM_001374736.1	MANE Select	c.4930-3641T>C		intron	N/A	NP_001361665.1	A0A7P0T890
	DST	NM_001374734.1		c.4957-3641T>C		intron	N/A	NP_001361663.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	ENST00000370765.11	TSL:1 MANE Plus Clinical	c.5909T>C	p.Phe1970Ser	missense	Exon 23 of 24	ENSP00000359801.6	Q03001-3
	DST	ENST00000680361.1	MANE Select	c.4930-3641T>C		intron	N/A	ENSP00000505098.1	A0A7P0T890
	DST	ENST00000244364.10	TSL:1	c.3319-3641T>C		intron	N/A	ENSP00000244364.6	Q03001-8

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

GnomAD2 exomes AF: 0.00434 AC: 1091 AN: 251226 AF XY: 0.00471

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 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

African (AFR) AF: 0.000627 AC: 21 AN: 33478

American (AMR) AF: 0.000984 AC: 44 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0108 AC: 928 AN: 86252

European-Finnish (FIN) AF: 0.00337 AC: 180 AN: 53414

Middle Eastern (MID) AF: 0.00763 AC: 44 AN: 5768

European-Non Finnish (NFE) AF: 0.00460 AC: 5120 AN: 1112002

Other (OTH) AF: 0.00373 AC: 225 AN: 60394

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

African (AFR) AF: 0.000698 AC: 29 AN: 41560

American (AMR) AF: 0.000654 AC: 10 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4816

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00491 AC: 334 AN: 68020

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00430 Hom.: 8

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Hereditary sensory and autonomic neuropathy type 6 (1)
-	-	1	Hereditary sensory and autonomic neuropathy type 6;C3809470:Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
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
PhyloP100		4.4
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
Mutation Taster		=92/8	polymorphism

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