rs869025395

Positions:

• chr6-7583113-C-G
• chr6-7583113-C-T

Variant summary

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

The NM_004415.4(DSP):​c.5851C>G​(p.Arg1951Gly) 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, single submitter U:1
• Conservation: PhyloP100: 3.70

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.5851C>G	p.Arg1951Gly	missense_variant	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.4522C>G	p.Arg1508Gly	missense_variant	24/24		NP_001305963.1
DSP	NM_001008844.3	c.4054C>G	p.Arg1352Gly	missense_variant	24/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.5851C>G	p.Arg1951Gly	missense_variant	24/24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.4054C>G	p.Arg1352Gly	missense_variant	24/24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.4522C>G	p.Arg1508Gly	missense_variant	24/24			ENSP00000518230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 02, 2019

This missense variant replaces arginine with glycine at codon 1951 of the DSP protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular 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	0.30
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.20	T;T
Polyphen		0.93	P;.
Vest4		0.73
MutPred		0.34		Loss of MoRF binding (P = 0.0441);.;
MVP		0.90
MPC		0.93
ClinPred		0.88	D
GERP RS		3.5
Varity_R		0.35
gMVP		0.56

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: rs869025395; hg19: chr6-7583346;