6-7541915-C-CA

Variant names:

• chr6-7541915-C-CA
• rs17133512
• NM_004415.4:c.1dupA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 8P and 9B. PVS1 BP6 BA1

The NM_004415.4(DSP):​c.1dupA​(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,609,250 control chromosomes in the GnomAD database, including 19,165 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.17 (2453 hom., cov: 30)
  • Exomes 𝑓: 0.15 (16712 hom.)
• Consequence: DSP NM_004415.4 frameshift, start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: 3.29
• Publications: 11 publications found

Genes affected

DSP (HGNC:3052): (desmoplakin) This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

DSP-AS1 (HGNC:56039): (DSP antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 718 pathogenic variants in the truncated region.
• BP6: Variant 6-7541915-C-CA is Benign according to our data. Variant chr6-7541915-C-CA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36015.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004415.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	NM_004415.4	MANE Select	c.1dupA	p.Met1fs	frameshift start_lost	Exon 1 of 24	NP_004406.2
	DSP	NM_001319034.2		c.1dupA	p.Met1fs	frameshift start_lost	Exon 1 of 24	NP_001305963.1
	DSP	NM_001008844.3		c.1dupA	p.Met1fs	frameshift start_lost	Exon 1 of 24	NP_001008844.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	ENST00000379802.8	TSL:1 MANE Select	c.1dupA	p.Met1fs	frameshift start_lost	Exon 1 of 24	ENSP00000369129.3
	DSP	ENST00000418664.3	TSL:1	c.1dupA	p.Met1fs	frameshift start_lost	Exon 1 of 24	ENSP00000396591.2
	DSP	ENST00000710359.2		c.1dupA	p.Met1fs	frameshift start_lost	Exon 1 of 24	ENSP00000518230.1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26256 AN: 152080 Hom.: 2450 Cov.: 30

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.156

GnomAD2 exomes AF: 0.167 AC: 38677 AN: 231420 AF XY: 0.161

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.262

Gnomad FIN exome AF: 0.174

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.149

GnomAD4 exome AF: 0.146 AC: 212018 AN: 1457052 Hom.: 16712 Cov.: 32 AF XY: 0.144 AC XY: 104253 AN XY: 724520

African (AFR) AF: 0.222 AC: 7426 AN: 33394

American (AMR) AF: 0.238 AC: 10553 AN: 44360

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2711 AN: 26046

East Asian (EAS) AF: 0.302 AC: 11958 AN: 39574

South Asian (SAS) AF: 0.125 AC: 10692 AN: 85634

European-Finnish (FIN) AF: 0.171 AC: 8810 AN: 51424

Middle Eastern (MID) AF: 0.0852 AC: 485 AN: 5692

European-Non Finnish (NFE) AF: 0.135 AC: 150468 AN: 1110760

Other (OTH) AF: 0.148 AC: 8915 AN: 60168

GnomAD4 genome AF: 0.173 AC: 26267 AN: 152198 Hom.: 2453 Cov.: 30 AF XY: 0.175 AC XY: 13040 AN XY: 74410

African (AFR) AF: 0.215 AC: 8915 AN: 41538

American (AMR) AF: 0.217 AC: 3314 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 379 AN: 3470

East Asian (EAS) AF: 0.269 AC: 1383 AN: 5138

South Asian (SAS) AF: 0.127 AC: 615 AN: 4826

European-Finnish (FIN) AF: 0.165 AC: 1751 AN: 10616

Middle Eastern (MID) AF: 0.0925 AC: 27 AN: 292

European-Non Finnish (NFE) AF: 0.138 AC: 9409 AN: 67990

Other (OTH) AF: 0.157 AC: 332 AN: 2114

Alfa AF: 0.127 Hom.: 1031

Bravo AF: 0.177

Asia WGS AF: 0.205 AC: 711 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	2	Cardiomyopathy (2)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	1	-	Arrhythmogenic right ventricular dysplasia 8 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Lethal acantholytic epidermolysis bullosa (1)
-	-	1	Woolly hair-skin fragility syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=99/1	polymorphism (auto)

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: rs17133512; hg19: chr6-7542148; COSMIC: COSV65791211; COSMIC: COSV65791211;