6-7582775-G-T

Position:

• chr6-7582775-G-T

Variant summary

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

The NM_004415.4(DSP):​c.5513G>T​(p.Arg1838Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar 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:3
• Conservation: PhyloP100: 5.59

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	Protein	UniProt
DSP	NM_004415.4	c.5513G>T	p.Arg1838Leu	missense_variant	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.4184G>T	p.Arg1395Leu	missense_variant	24/24		NP_001305963.1
DSP	NM_001008844.3	c.3716G>T	p.Arg1239Leu	missense_variant	24/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.5513G>T	p.Arg1838Leu	missense_variant	24/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.3716G>T	p.Arg1239Leu	missense_variant	24/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.4184G>T	p.Arg1395Leu	missense_variant	24/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

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

Mar 23, 2023

This missense variant replaces arginine with leucine at codon 1838 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. -

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

Jan 12, 2024

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1838 of the DSP protein (p.Arg1838Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DSP-related conditions. ClinVar contains an entry for this variant (Variation ID: 629371). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 28, 2023

This missense variant replaces arginine with leucine at codon 1838 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Benign	0.19
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.058	T;T
Polyphen		0.22	B;.
Vest4		0.76
MutPred		0.15		Loss of MoRF binding (P = 0.0133);.;
MVP		0.57
MPC		0.39
ClinPred		0.97	D
GERP RS		4.3
Varity_R		0.26
gMVP		0.40

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: rs377715841; hg19: chr6-7583008;