rs200409452

chr6-7571880-G-T

Variant summary

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

The NM_004415.4(DSP):c.1942G>T(p.Asp648Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D648V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.16

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.1942G>T	p.Asp648Tyr	missense_variant	15/24	ENST00000379802.8
DSP	NM_001319034.2	c.1942G>T	p.Asp648Tyr	missense_variant	15/24
DSP	NM_001008844.3	c.1942G>T	p.Asp648Tyr	missense_variant	15/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.1942G>T	p.Asp648Tyr	missense_variant	15/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.1942G>T	p.Asp648Tyr	missense_variant	15/24	1		A2
DSP	ENST00000710359.1	c.1942G>T	p.Asp648Tyr	missense_variant	15/24			A2
DSP	ENST00000684395.1	n.583G>T		non_coding_transcript_exon_variant	2/5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 26, 2023

This missense variant replaces aspartic acid with tyrosine at codon 648 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSP-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	0.038
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N;D
REVEL	Benign	0.23
Sift	Benign	0.038	D;D
Sift4G	Uncertain	0.033	D;D
Polyphen		0.12	B;.
Vest4		0.60
MutPred		0.44		Loss of disorder (P = 0.0224);Loss of disorder (P = 0.0224);
MVP		0.82
MPC		0.34
ClinPred		0.48	T
GERP RS		5.6
Varity_R		0.19
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200409452; hg19: chr6-7572113;