NM_001374736.1:c.*253C>A

Variant names:

• chr6-56458752-G-T
• rs79455288
• NM_001374736.1:c.*253C>A

Variant summary

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

The NM_001374736.1(DST):​c.*253C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 321,888 control chromosomes in the GnomAD database, including 219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (81 hom., cov: 32)
  • Exomes 𝑓: 0.034 (138 hom.)
• Consequence: DST NM_001374736.1 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.485
• Publications: 2 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 (BayesDel_noAF=-0.89).
• BP6: Variant 6-56458752-G-T is Benign according to our data. Variant chr6-56458752-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1300301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0294 (4466/152158) while in subpopulation NFE AF = 0.0423 (2875/68000). AF 95% confidence interval is 0.041. There are 81 homozygotes in GnomAd4. There are 2001 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 81 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374736.1. 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_001374736.1	MANE Select	c.*253C>A		3_prime_UTR	Exon 104 of 104	NP_001361665.1	A0A7P0T890
	DST	NM_001374734.1		c.*253C>A		3_prime_UTR	Exon 103 of 103	NP_001361663.1
	DST	NM_001374722.1		c.*253C>A		3_prime_UTR	Exon 103 of 103	NP_001361651.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	ENST00000680361.1	MANE Select	c.*253C>A		3_prime_UTR	Exon 104 of 104	ENSP00000505098.1	A0A7P0T890
	DST	ENST00000244364.10	TSL:1	c.*253C>A		3_prime_UTR	Exon 84 of 84	ENSP00000244364.6	Q03001-8
	DST	ENST00000523292.5	TSL:1	c.*253C>A		3_prime_UTR	Exon 5 of 5	ENSP00000431020.1	H0YC65

Frequencies

GnomAD3 genomes AF: 0.0293 AC: 4461 AN: 152040 Hom.: 82 Cov.: 32

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.0478

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0157

Gnomad FIN AF: 0.00963

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0423

Gnomad OTH AF: 0.0263

GnomAD4 exome AF: 0.0336 AC: 5697 AN: 169730 Hom.: 138 Cov.: 3 AF XY: 0.0330 AC XY: 2857 AN XY: 86642

African (AFR) AF: 0.0250 AC: 139 AN: 5568

American (AMR) AF: 0.0178 AC: 118 AN: 6638

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 284 AN: 6238

East Asian (EAS) AF: 0.0000747 AC: 1 AN: 13394

South Asian (SAS) AF: 0.0160 AC: 123 AN: 7666

European-Finnish (FIN) AF: 0.0146 AC: 122 AN: 8334

Middle Eastern (MID) AF: 0.00472 AC: 4 AN: 848

European-Non Finnish (NFE) AF: 0.0410 AC: 4522 AN: 110230

Other (OTH) AF: 0.0355 AC: 384 AN: 10814

GnomAD4 genome AF: 0.0294 AC: 4466 AN: 152158 Hom.: 81 Cov.: 32 AF XY: 0.0269 AC XY: 2001 AN XY: 74382

African (AFR) AF: 0.0233 AC: 968 AN: 41512

American (AMR) AF: 0.0145 AC: 221 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0478 AC: 166 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.0158 AC: 76 AN: 4822

European-Finnish (FIN) AF: 0.00963 AC: 102 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0423 AC: 2875 AN: 68000

Other (OTH) AF: 0.0261 AC: 55 AN: 2110

Alfa AF: 0.0272 Hom.: 26

Bravo AF: 0.0297

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.52
PhyloP100		0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs79455288; hg19: chr6-56323550;