rs80325569

Variant names:

• chr6-7576980-G-A
• rs80325569
• NM_004415.4:c.2815G>A

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.2815G>A​(p.Gly939Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00209 in 1,613,254 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. G939G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (29 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (33 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 3.83
• Publications: 5 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=0.00688228).
• BP6: Variant 6-7576980-G-A is Benign according to our data. Variant chr6-7576980-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0113 (1722/152212) while in subpopulation AFR AF = 0.0397 (1647/41518). AF 95% confidence interval is 0.0381. There are 29 homozygotes in GnomAd4. There are 825 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 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.2815G>A	p.Gly939Ser	missense	Exon 20 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.2815G>A	p.Gly939Ser	missense	Exon 20 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.2815G>A	p.Gly939Ser	missense	Exon 20 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.2815G>A	p.Gly939Ser	missense	Exon 20 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.2815G>A	p.Gly939Ser	missense	Exon 20 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000713904.1		c.2689G>A	p.Gly897Ser	missense	Exon 20 of 24	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1715 AN: 152094 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00289 AC: 725 AN: 251034 AF XY: 0.00217

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00113 AC: 1652 AN: 1461042 Hom.: 33 Cov.: 30 AF XY: 0.000965 AC XY: 701 AN XY: 726718

African (AFR) AF: 0.0412 AC: 1378 AN: 33444

American (AMR) AF: 0.00188 AC: 84 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5766

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111536

Other (OTH) AF: 0.00222 AC: 134 AN: 60354

GnomAD4 genome AF: 0.0113 AC: 1722 AN: 152212 Hom.: 29 Cov.: 33 AF XY: 0.0111 AC XY: 825 AN XY: 74406

African (AFR) AF: 0.0397 AC: 1647 AN: 41518

American (AMR) AF: 0.00307 AC: 47 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68004

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00468 Hom.: 24

Bravo AF: 0.0131

ESP6500AA AF: 0.0390 AC: 172

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00366 AC: 444

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	6	not specified (6)
-	-	3	Cardiomyopathy (3)
-	-	2	Arrhythmogenic right ventricular 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	0.085
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.010
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.61	N
PhyloP100		3.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.064
Sift	Benign	0.53	T
Sift4G	Benign	0.69	T
Polyphen		0.0010	B
Vest4		0.50
MVP		0.38
MPC		0.24
ClinPred		0.011	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.060
gMVP		0.29
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs80325569; hg19: chr6-7577213;