rs6929069

Variant names:

• chr6-7581403-G-A
• rs6929069
• NM_004415.4:c.5213G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-7581403-G-A
• chr6-7581403-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004415.4(DSP):​c.5213G>A​(p.Arg1738Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,616 control chromosomes in the GnomAD database, including 21,037 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1738G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.20 (3497 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17540 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.629
• Publications: 33 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004233688).
• BP6: Variant 6-7581403-G-A is Benign according to our data. Variant chr6-7581403-G-A is described in ClinVar as Benign. ClinVar VariationId is 44925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.32 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.5213G>A	p.Arg1738Gln	missense	Exon 23 of 24	NP_004406.2
	DSP	NM_001319034.2		c.4050+1163G>A		intron	N/A	NP_001305963.1
	DSP	NM_001008844.3		c.3583-1239G>A		intron	N/A	NP_001008844.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	ENST00000379802.8	TSL:1 MANE Select	c.5213G>A	p.Arg1738Gln	missense	Exon 23 of 24	ENSP00000369129.3
	DSP	ENST00000418664.3	TSL:1	c.3583-1239G>A		intron	N/A	ENSP00000396591.2
	DSP	ENST00000713904.1		c.5087G>A	p.Arg1696Gln	missense	Exon 23 of 24	ENSP00000519203.1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29704 AN: 152008 Hom.: 3491 Cov.: 32

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.0670

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.175

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.181

GnomAD2 exomes AF: 0.172 AC: 43268 AN: 251186 AF XY: 0.170

Gnomad AFR exome AF: 0.330

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.195

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.147 AC: 215412 AN: 1461490 Hom.: 17540 Cov.: 34 AF XY: 0.149 AC XY: 108288 AN XY: 727086

African (AFR) AF: 0.342 AC: 11405 AN: 33368

American (AMR) AF: 0.194 AC: 8637 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 4169 AN: 26128

East Asian (EAS) AF: 0.185 AC: 7326 AN: 39700

South Asian (SAS) AF: 0.234 AC: 20182 AN: 86228

European-Finnish (FIN) AF: 0.172 AC: 9177 AN: 53412

Middle Eastern (MID) AF: 0.193 AC: 1111 AN: 5768

European-Non Finnish (NFE) AF: 0.129 AC: 143588 AN: 1111904

Other (OTH) AF: 0.163 AC: 9817 AN: 60360

GnomAD4 genome AF: 0.196 AC: 29745 AN: 152126 Hom.: 3497 Cov.: 32 AF XY: 0.197 AC XY: 14666 AN XY: 74374

African (AFR) AF: 0.324 AC: 13455 AN: 41484

American (AMR) AF: 0.179 AC: 2741 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 528 AN: 3472

East Asian (EAS) AF: 0.201 AC: 1040 AN: 5180

South Asian (SAS) AF: 0.234 AC: 1127 AN: 4816

European-Finnish (FIN) AF: 0.178 AC: 1879 AN: 10572

Middle Eastern (MID) AF: 0.164 AC: 48 AN: 292

European-Non Finnish (NFE) AF: 0.125 AC: 8474 AN: 67994

Other (OTH) AF: 0.185 AC: 392 AN: 2116

Alfa AF: 0.152 Hom.: 7142

Bravo AF: 0.201

TwinsUK AF: 0.141 AC: 521

ALSPAC AF: 0.135 AC: 519

ESP6500AA AF: 0.328 AC: 1444

ESP6500EA AF: 0.126 AC: 1081

ExAC AF: 0.172 AC: 20898

Asia WGS AF: 0.265 AC: 924 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	not provided (3)
-	-	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	Woolly hair-skin fragility syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N
PhyloP100		0.63
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.066
Sift	Benign	0.076	T
Sift4G	Benign	0.18	T
Polyphen		0.0030	B
Vest4		0.090
MPC		0.27
ClinPred		0.0019	T
GERP RS		3.2
Varity_R		0.049
gMVP		0.33
Mutation Taster		=96/4	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: rs6929069; hg19: chr6-7581636; COSMIC: COSV65791527;