rs78701610

Variant names:

• chr6-56619745-G-A
• rs78701610
• NM_001723.7:c.4289C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-56619745-G-A
• chr6-56619745-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001723.7(DST):​c.4289C>T​(p.Ala1430Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,614,056 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1430A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (22 hom.)
• Consequence: DST NM_001723.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.515
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024791658).
• BP6: Variant 6-56619745-G-A is Benign according to our data. Variant chr6-56619745-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 357576.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 = 0.0101 (1540/152236) while in subpopulation AFR AF = 0.0345 (1434/41556). AF 95% confidence interval is 0.033. There are 27 homozygotes in GnomAd4. There are 740 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 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.4289C>T	p.Ala1430Val	missense	Exon 23 of 24	NP_001714.1	Q03001-3
	DST	NM_001374736.1	MANE Select	c.4929+4785C>T		intron	N/A	NP_001361665.1	A0A7P0T890
	DST	NM_001374734.1		c.4956+4785C>T		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.4289C>T	p.Ala1430Val	missense	Exon 23 of 24	ENSP00000359801.6	Q03001-3
	DST	ENST00000680361.1	MANE Select	c.4929+4785C>T		intron	N/A	ENSP00000505098.1	A0A7P0T890
	DST	ENST00000244364.10	TSL:1	c.3318+4785C>T		intron	N/A	ENSP00000244364.6	Q03001-8

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1539 AN: 152118 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00254 AC: 639 AN: 251328 AF XY: 0.00159

Gnomad AFR exome AF: 0.0333

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00108 AC: 1574 AN: 1461820 Hom.: 22 Cov.: 36 AF XY: 0.000927 AC XY: 674 AN XY: 727208

African (AFR) AF: 0.0344 AC: 1151 AN: 33480

American (AMR) AF: 0.00235 AC: 105 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.000127 AC: 141 AN: 1112010

Other (OTH) AF: 0.00238 AC: 144 AN: 60394

GnomAD4 genome AF: 0.0101 AC: 1540 AN: 152236 Hom.: 27 Cov.: 32 AF XY: 0.00994 AC XY: 740 AN XY: 74434

African (AFR) AF: 0.0345 AC: 1434 AN: 41556

American (AMR) AF: 0.00537 AC: 82 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68010

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00349 Hom.: 14

Bravo AF: 0.0114

ESP6500AA AF: 0.0370 AC: 163

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00311 AC: 377

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	Benign	0.074
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.4
DANN	Benign	0.57
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.93	T
PhyloP100		0.52
PROVEAN	Benign	0.54	N
REVEL	Benign	0.030
Sift	Benign	0.32	T
Sift4G	Benign	0.35	T
Polyphen		0.0010	B
Vest4		0.14
MVP		0.11
ClinPred		0.0011	T
GERP RS		-3.3
Mutation Taster		=99/1	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: rs78701610; hg19: chr6-56484543;