6-7580799-C-T

Variant names:

• chr6-7580799-C-T
• rs28763967
• NM_004415.4:c.4609C>T

Variant summary

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

The NM_004415.4(DSP):​c.4609C>T​(p.Arg1537Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,614,112 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1537H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0090 (8 hom., cov: 32)
  • Exomes 𝑓: 0.014 (181 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 2.08
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009360015).
• BP6: Variant 6-7580799-C-T is Benign according to our data. Variant chr6-7580799-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44917.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 = 0.00895 (1363/152284) while in subpopulation NFE AF = 0.0156 (1062/68026). AF 95% confidence interval is 0.0148. There are 8 homozygotes in GnomAd4. There are 590 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	NM_004415.4	MANE Select	c.4609C>T	p.Arg1537Cys	missense	Exon 23 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.4050+559C>T		intron	N/A	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.3582+1027C>T		intron	N/A	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.4609C>T	p.Arg1537Cys	missense	Exon 23 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.3582+1027C>T		intron	N/A	ENSP00000396591.2	P15924-2
	DSP	ENST00000713904.1		c.4483C>T	p.Arg1495Cys	missense	Exon 23 of 24	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes AF: 0.00895 AC: 1362 AN: 152166 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0156

Gnomad OTH AF: 0.00815

GnomAD2 exomes AF: 0.00879 AC: 2201 AN: 250280 AF XY: 0.00858

Gnomad AFR exome AF: 0.00280

Gnomad AMR exome AF: 0.00686

Gnomad ASJ exome AF: 0.00140

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00448

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.0128

GnomAD4 exome AF: 0.0136 AC: 19943 AN: 1461828 Hom.: 181 Cov.: 32 AF XY: 0.0132 AC XY: 9629 AN XY: 727204

African (AFR) AF: 0.00212 AC: 71 AN: 33480

American (AMR) AF: 0.00740 AC: 331 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000707 AC: 61 AN: 86258

European-Finnish (FIN) AF: 0.00395 AC: 211 AN: 53358

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0167 AC: 18531 AN: 1112008

Other (OTH) AF: 0.0116 AC: 703 AN: 60396

GnomAD4 genome AF: 0.00895 AC: 1363 AN: 152284 Hom.: 8 Cov.: 32 AF XY: 0.00792 AC XY: 590 AN XY: 74470

African (AFR) AF: 0.00354 AC: 147 AN: 41562

American (AMR) AF: 0.00589 AC: 90 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00377 AC: 40 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0156 AC: 1062 AN: 68026

Other (OTH) AF: 0.00806 AC: 17 AN: 2108

Alfa AF: 0.0130 Hom.: 61

Bravo AF: 0.00939

TwinsUK AF: 0.0170 AC: 63

ALSPAC AF: 0.0171 AC: 66

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0143 AC: 123

ExAC AF: 0.00904 AC: 1098

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0129

EpiControl AF: 0.0140

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	6	not provided (6)
-	-	2	Arrhythmogenic right ventricular dysplasia 8 (2)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy;C1142166:Brugada syndrome (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Lethal acantholytic epidermolysis bullosa (1)
-	-	1	Woolly hair-skin fragility syndrome (1)
-	-	1	Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0094	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.054	T
Polyphen		1.0	D
Vest4		0.48
MVP		0.59
MPC		0.30
ClinPred		0.0088	T
GERP RS		5.8
Varity_R		0.15
gMVP		0.22
Mutation Taster		=84/16	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: rs28763967; hg19: chr6-7581032;