6-56619985-G-A

Variant names:

• chr6-56619985-G-A
• rs45472691
• NM_001723.7:c.4049C>T

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.4049C>T​(p.Thr1350Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,613,928 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1350T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: DST NM_001723.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -1.34
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005272925).
• BP6: Variant 6-56619985-G-A is Benign according to our data. Variant chr6-56619985-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 357581.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00129 (196/152130) while in subpopulation NFE AF = 0.00151 (103/67998). AF 95% confidence interval is 0.00128. There are 0 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.4049C>T	p.Thr1350Met	missense	Exon 23 of 24	NP_001714.1	Q03001-3
	DST	NM_001374736.1	MANE Select	c.4929+4545C>T		intron	N/A	NP_001361665.1	A0A7P0T890
	DST	NM_001374734.1		c.4956+4545C>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.4049C>T	p.Thr1350Met	missense	Exon 23 of 24	ENSP00000359801.6	Q03001-3
	DST	ENST00000680361.1	MANE Select	c.4929+4545C>T		intron	N/A	ENSP00000505098.1	A0A7P0T890
	DST	ENST00000244364.10	TSL:1	c.3318+4545C>T		intron	N/A	ENSP00000244364.6	Q03001-8

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 152012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00634

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00158 AC: 397 AN: 251154 AF XY: 0.00167

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00648

Gnomad NFE exome AF: 0.00168

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00150 AC: 2192 AN: 1461798 Hom.: 3 Cov.: 34 AF XY: 0.00151 AC XY: 1097 AN XY: 727206

African (AFR) AF: 0.000329 AC: 11 AN: 33478

American (AMR) AF: 0.000268 AC: 12 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00421 AC: 110 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86256

European-Finnish (FIN) AF: 0.00641 AC: 342 AN: 53366

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00143 AC: 1590 AN: 1111982

Other (OTH) AF: 0.00166 AC: 100 AN: 60394

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.00148 AC XY: 110 AN XY: 74356

African (AFR) AF: 0.000145 AC: 6 AN: 41516

American (AMR) AF: 0.000262 AC: 4 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00634 AC: 67 AN: 10572

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00151 AC: 103 AN: 67998

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00141 Hom.: 1

Bravo AF: 0.000858

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00155 AC: 188

EpiCase AF: 0.00191

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	DST-related disorder (1)
-	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	0.085
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.52
DANN	Benign	0.78
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.97	T
PhyloP100		-1.3
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.018
Sift	Benign	0.14	T
Sift4G	Benign	0.099	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.13
ClinPred		0.0037	T
GERP RS		0.57
Mutation Taster		=97/3	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: rs45472691; hg19: chr6-56484783;