NM_004415.4:c.3510G>A

Variant names:

• chr6-7579700-G-A
• rs28763964
• NM_004415.4:c.3510G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004415.4(DSP):​c.3510G>A​(p.Glu1170Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,613,794 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (21 hom.)
• Consequence: DSP NM_004415.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.95
• Publications: 3 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=-0.48).
• BP6: Variant 6-7579700-G-A is Benign according to our data. Variant chr6-7579700-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.95 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00931 (1417/152210) while in subpopulation AFR AF = 0.0326 (1354/41532). AF 95% confidence interval is 0.0312. There are 19 homozygotes in GnomAd4. There are 674 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AD,AR gene

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.3510G>A	p.Glu1170Glu	synonymous	Exon 23 of 24	NP_004406.2
	DSP	NM_001319034.2		c.3510G>A	p.Glu1170Glu	synonymous	Exon 23 of 24	NP_001305963.1
	DSP	NM_001008844.3		c.3510G>A	p.Glu1170Glu	synonymous	Exon 23 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.3510G>A	p.Glu1170Glu	synonymous	Exon 23 of 24	ENSP00000369129.3
	DSP	ENST00000418664.3	TSL:1	c.3510G>A	p.Glu1170Glu	synonymous	Exon 23 of 24	ENSP00000396591.2
	DSP	ENST00000713904.1		c.3384G>A	p.Glu1128Glu	synonymous	Exon 23 of 24	ENSP00000519203.1

Frequencies

GnomAD3 genomes AF: 0.00928 AC: 1411 AN: 152092 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00244 AC: 611 AN: 250424 AF XY: 0.00184

Gnomad AFR exome AF: 0.0330

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000796

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000965 AC: 1411 AN: 1461584 Hom.: 21 Cov.: 32 AF XY: 0.000840 AC XY: 611 AN XY: 727096

African (AFR) AF: 0.0346 AC: 1158 AN: 33466

American (AMR) AF: 0.00174 AC: 78 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111818

Other (OTH) AF: 0.00190 AC: 115 AN: 60382

GnomAD4 genome AF: 0.00931 AC: 1417 AN: 152210 Hom.: 19 Cov.: 32 AF XY: 0.00906 AC XY: 674 AN XY: 74400

African (AFR) AF: 0.0326 AC: 1354 AN: 41532

American (AMR) AF: 0.00262 AC: 40 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68016

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00685 Hom.: 9

Bravo AF: 0.0109

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Cardiomyopathy (2)
-	-	2	not provided (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	Woolly hair-skin fragility syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.2
DANN	Benign	0.50
PhyloP100		1.9
Mutation Taster		=96/4	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: rs28763964; hg19: chr6-7579933;