rs869025392

Positions:

• chr6-7580993-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_004415.4(DSP):​c.4803G>A​(p.Met1601Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7580993-G-A is Pathogenic according to our data. Variant chr6-7580993-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 222578.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.4803G>A	p.Met1601Ile	missense_variant	23/24	ENST00000379802.8	NP_004406.2
DSP	NM_001008844.3	c.3582+1221G>A		intron_variant			NP_001008844.1
DSP	NM_001319034.2	c.4050+753G>A		intron_variant			NP_001305963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.4803G>A	p.Met1601Ile	missense_variant	23/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.3582+1221G>A		intron_variant		1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.4050+753G>A		intron_variant				ENSP00000518230	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	Rampazzo Lab, Human Molecular Genetics Unit, University of Padua	Apr 18, 2017	This missense mutation is absent in all consulted databases of genetic variations (dbSNP, 1000Genomes, EVS and ExAC) and involves a highly conserved residue in the central rod domain. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 14, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.046
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.22
Sift	Benign	0.31	T
Sift4G	Benign	0.28	T
Polyphen		0.0090	B
Vest4		0.83
MutPred		0.19		Loss of ubiquitination at K1606 (P = 0.0496);
MVP		0.90
MPC		0.24
ClinPred		0.78	D
GERP RS		5.9
Varity_R		0.11
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs869025392; hg19: chr6-7581226; COSMIC: COSV104692925;