rs78652302

Variant names:

• chr6-7582760-A-T
• rs78652302
• NM_004415.4:c.5498A>T

Your query was ambiguous. Multiple possible variants found:

• chr6-7582760-A-T
• chr6-7582760-A-G

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.5498A>T​(p.Glu1833Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,613,852 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E1833E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0087 (11 hom., cov: 32)
  • Exomes 𝑓: 0.011 (105 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:25
• Conservation: PhyloP100: 7.45
• Publications: 19 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=0.0074617565).
• BP6: Variant 6-7582760-A-T is Benign according to our data. Variant chr6-7582760-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44929.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 = 0.00869 (1323/152240) while in subpopulation NFE AF = 0.0128 (873/68010). AF 95% confidence interval is 0.0121. There are 11 homozygotes in GnomAd4. There are 647 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.5498A>T	p.Glu1833Val	missense	Exon 24 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.4169A>T	p.Glu1390Val	missense	Exon 24 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.3701A>T	p.Glu1234Val	missense	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.5498A>T	p.Glu1833Val	missense	Exon 24 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.3701A>T	p.Glu1234Val	missense	Exon 24 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000713904.1		c.5372A>T	p.Glu1791Val	missense	Exon 24 of 24	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes AF: 0.00870 AC: 1323 AN: 152122 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00808

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00935 AC: 2349 AN: 251172 AF XY: 0.00921

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00685

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.0135

Gnomad OTH exome AF: 0.00881

GnomAD4 exome AF: 0.0109 AC: 15906 AN: 1461612 Hom.: 105 Cov.: 31 AF XY: 0.0106 AC XY: 7728 AN XY: 727068

African (AFR) AF: 0.00200 AC: 67 AN: 33464

American (AMR) AF: 0.00369 AC: 165 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00834 AC: 218 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000499 AC: 43 AN: 86244

European-Finnish (FIN) AF: 0.0251 AC: 1340 AN: 53418

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.0121 AC: 13463 AN: 1111802

Other (OTH) AF: 0.0100 AC: 604 AN: 60380

GnomAD4 genome AF: 0.00869 AC: 1323 AN: 152240 Hom.: 11 Cov.: 32 AF XY: 0.00869 AC XY: 647 AN XY: 74424

African (AFR) AF: 0.00193 AC: 80 AN: 41536

American (AMR) AF: 0.00575 AC: 88 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00808 AC: 28 AN: 3466

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

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4822

European-Finnish (FIN) AF: 0.0221 AC: 235 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0128 AC: 873 AN: 68010

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.0109 Hom.: 5

Bravo AF: 0.00707

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0130 AC: 112

ExAC AF: 0.00943 AC: 1145

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0110

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	10	not specified (11)
-	-	4	not provided (4)
-	-	2	Cardiomyopathy (2)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	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	Hypertrophic cardiomyopathy 2 (1)
-	-	1	Hypertrophic cardiomyopathy;C0023976:Long QT syndrome;C0878544:Cardiomyopathy (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	Uncertain	0.54
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.5
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.24
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.71
MVP		0.62
MPC		0.89
ClinPred		0.0079	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.53
Mutation Taster		=74/26	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: rs78652302; hg19: chr6-7582993;