NM_004415.4:c.2631G>A

Variant names:

• chr6-7576294-G-A
• rs1016835
• NM_004415.4:c.2631G>A

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.2631G>A​(p.Arg877Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.782 in 1,612,944 control chromosomes in the GnomAD database, including 495,137 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R877R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.75 (43138 hom., cov: 32)
  • Exomes 𝑓: 0.79 (451999 hom.)
• Consequence: DSP NM_004415.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001223
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 0.269
• Publications: 26 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):

• arrhythmogenic right ventricular dysplasia 8

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• keratosis palmoplantaris striata 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp
• skin fragility-woolly hair-palmoplantar keratoderma syndrome

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

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Orphanet, Ambry Genetics
• cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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=-0.57).
• BP6: Variant 6-7576294-G-A is Benign according to our data. Variant chr6-7576294-G-A is described in ClinVar as Benign. ClinVar VariationId is 44877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.269 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.792 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.2631G>A	p.Arg877Arg	splice_region synonymous	Exon 19 of 24	NP_004406.2
	DSP	NM_001319034.2		c.2631G>A	p.Arg877Arg	splice_region synonymous	Exon 19 of 24	NP_001305963.1
	DSP	NM_001008844.3		c.2631G>A	p.Arg877Arg	splice_region synonymous	Exon 19 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.2631G>A	p.Arg877Arg	splice_region synonymous	Exon 19 of 24	ENSP00000369129.3
	DSP	ENST00000418664.3	TSL:1	c.2631G>A	p.Arg877Arg	splice_region synonymous	Exon 19 of 24	ENSP00000396591.2
	DSP	ENST00000713904.1		c.2505G>A	p.Arg835Arg	splice_region synonymous	Exon 19 of 24	ENSP00000519203.1

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113851 AN: 151938 Hom.: 43118 Cov.: 32

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.863

Gnomad AMR AF: 0.793

Gnomad ASJ AF: 0.825

Gnomad EAS AF: 0.799

Gnomad SAS AF: 0.747

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.798

Gnomad OTH AF: 0.776

GnomAD2 exomes AF: 0.775 AC: 194456 AN: 251060 AF XY: 0.777

Gnomad AFR exome AF: 0.642

Gnomad AMR exome AF: 0.785

Gnomad ASJ exome AF: 0.817

Gnomad EAS exome AF: 0.803

Gnomad FIN exome AF: 0.718

Gnomad NFE exome AF: 0.801

Gnomad OTH exome AF: 0.786

GnomAD4 exome AF: 0.786 AC: 1147720 AN: 1460886 Hom.: 451999 Cov.: 43 AF XY: 0.786 AC XY: 570968 AN XY: 726784

African (AFR) AF: 0.631 AC: 21124 AN: 33454

American (AMR) AF: 0.789 AC: 35283 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.815 AC: 21281 AN: 26124

East Asian (EAS) AF: 0.812 AC: 32221 AN: 39670

South Asian (SAS) AF: 0.745 AC: 64195 AN: 86220

European-Finnish (FIN) AF: 0.719 AC: 38396 AN: 53390

Middle Eastern (MID) AF: 0.796 AC: 4584 AN: 5762

European-Non Finnish (NFE) AF: 0.795 AC: 883370 AN: 1111206

Other (OTH) AF: 0.783 AC: 47266 AN: 60350

GnomAD4 genome AF: 0.749 AC: 113923 AN: 152058 Hom.: 43138 Cov.: 32 AF XY: 0.748 AC XY: 55609 AN XY: 74324

African (AFR) AF: 0.645 AC: 26749 AN: 41448

American (AMR) AF: 0.793 AC: 12119 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.825 AC: 2862 AN: 3470

East Asian (EAS) AF: 0.798 AC: 4122 AN: 5164

South Asian (SAS) AF: 0.747 AC: 3599 AN: 4816

European-Finnish (FIN) AF: 0.716 AC: 7572 AN: 10576

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.798 AC: 54239 AN: 67984

Other (OTH) AF: 0.771 AC: 1632 AN: 2116

Alfa AF: 0.788 Hom.: 211957

Bravo AF: 0.751

Asia WGS AF: 0.727 AC: 2526 AN: 3478

EpiCase AF: 0.818

EpiControl AF: 0.808

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Cardiomyopathy (2)
-	-	2	Lethal acantholytic epidermolysis bullosa (2)
-	-	2	Woolly hair-skin fragility syndrome (2)
-	-	1	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 8 (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Keratosis palmoplantaris striata 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.7
DANN	Benign	0.70
PhyloP100		0.27
Mutation Taster		=66/34	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.030
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: rs1016835; hg19: chr6-7576527; COSMIC: COSV65794284;