rs11558731

Variant names:

• chr6-7585437-C-A
• rs11558731
• NM_004415.4:c.8175C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-7585437-C-A
• chr6-7585437-C-G
• chr6-7585437-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004415.4(DSP):​c.8175C>A​(p.Arg2725Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0561 in 1,614,098 control chromosomes in the GnomAD database, including 2,881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (207 hom., cov: 32)
  • Exomes 𝑓: 0.057 (2674 hom.)
• Consequence: DSP NM_004415.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.876
• Publications: 6 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 Gene-Disease associations (from GenCC):

• keratosis palmoplantaris striata 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, G2P
• arrhythmogenic cardiomyopathy with wooly hair and keratoderma

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen
• arrhythmogenic right ventricular dysplasia 8

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• skin fragility-woolly hair-palmoplantar keratoderma syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, G2P, Ambry Genetics, Orphanet
• cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• lethal acantholytic epidermolysis bullosa

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• striate palmoplantar keratoderma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe dermatitis-multiple allergies-metabolic wasting syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 6-7585437-C-A is Benign according to our data. Variant chr6-7585437-C-A is described in ClinVar as Benign. ClinVar VariationId is 44961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.876 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0631 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	NM_004415.4	MANE Select	c.8175C>A	p.Arg2725Arg	synonymous	Exon 24 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.6846C>A	p.Arg2282Arg	synonymous	Exon 24 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.6378C>A	p.Arg2126Arg	synonymous	Exon 24 of 24	NP_001008844.1	P15924-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	ENST00000379802.8	TSL:1 MANE Select	c.8175C>A	p.Arg2725Arg	synonymous	Exon 24 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.6378C>A	p.Arg2126Arg	synonymous	Exon 24 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000713904.1		c.8049C>A	p.Arg2683Arg	synonymous	Exon 24 of 24	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes AF: 0.0431 AC: 6556 AN: 152094 Hom.: 207 Cov.: 32

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0491

Gnomad ASJ AF: 0.0698

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0457

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0647

Gnomad OTH AF: 0.0504

GnomAD2 exomes AF: 0.0460 AC: 11573 AN: 251438 AF XY: 0.0465

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.0345

Gnomad ASJ exome AF: 0.0664

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0466

Gnomad NFE exome AF: 0.0673

Gnomad OTH exome AF: 0.0538

GnomAD4 exome AF: 0.0575 AC: 84054 AN: 1461886 Hom.: 2674 Cov.: 38 AF XY: 0.0567 AC XY: 41252 AN XY: 727244

African (AFR) AF: 0.00896 AC: 300 AN: 33480

American (AMR) AF: 0.0372 AC: 1664 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0662 AC: 1729 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0185 AC: 1597 AN: 86258

European-Finnish (FIN) AF: 0.0473 AC: 2529 AN: 53416

Middle Eastern (MID) AF: 0.0407 AC: 235 AN: 5768

European-Non Finnish (NFE) AF: 0.0656 AC: 72920 AN: 1112008

Other (OTH) AF: 0.0509 AC: 3074 AN: 60396

GnomAD4 genome AF: 0.0430 AC: 6551 AN: 152212 Hom.: 207 Cov.: 32 AF XY: 0.0430 AC XY: 3203 AN XY: 74428

African (AFR) AF: 0.0108 AC: 448 AN: 41540

American (AMR) AF: 0.0490 AC: 749 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0698 AC: 242 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0176 AC: 85 AN: 4820

European-Finnish (FIN) AF: 0.0457 AC: 484 AN: 10602

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0647 AC: 4399 AN: 68008

Other (OTH) AF: 0.0494 AC: 104 AN: 2106

Alfa AF: 0.0563 Hom.: 121

Bravo AF: 0.0428

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.0670

EpiControl AF: 0.0681

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Cardiomyopathy (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 8 (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Lethal acantholytic epidermolysis bullosa (1)
-	-	1	not provided (1)
-	-	1	Woolly hair-skin fragility syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	9.5
DANN	Benign	0.84
PhyloP100		0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=71/29	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: rs11558731; hg19: chr6-7585670; COSMIC: COSV60940795; COSMIC: COSV60940795;