6-7568444-G-T

Position:

• chr6-7568444-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004415.4(DSP):​c.1274G>T​(p.Arg425Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.64

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.1274G>T	p.Arg425Leu	missense_variant	11/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1274G>T	p.Arg425Leu	missense_variant	11/24		NP_001305963.1
DSP	NM_001008844.3	c.1274G>T	p.Arg425Leu	missense_variant	11/24		NP_001008844.1
DSP	NM_001406591.1	c.1274G>T	p.Arg425Leu	missense_variant	11/11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1274G>T	p.Arg425Leu	missense_variant	11/24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.1274G>T	p.Arg425Leu	missense_variant	11/24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.1274G>T	p.Arg425Leu	missense_variant	11/24			ENSP00000518230.1
DSP	ENST00000682228.1	n.1459G>T		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461754 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 26, 2021

This sequence change replaces arginine with leucine at codon 425 of the DSP protein (p.Arg425Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with DSP-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.5	L;L
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.010	D;T
Polyphen		0.31	B;.
Vest4		0.71
MutPred		0.36		Loss of ubiquitination at K427 (P = 0.0367);Loss of ubiquitination at K427 (P = 0.0367);
MVP		0.83
MPC		0.29
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.72
gMVP		0.61

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: rs397516916; hg19: chr6-7568677;