rs773113214

chr6-7581209-A-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_004415.4(DSP):c.5019A>T(p.Glu1673Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -1.74

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03421989).
• BP6: Variant 6-7581209-A-T is Benign according to our data. Variant chr6-7581209-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 570496.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.5019A>T	p.Glu1673Asp	missense_variant	23/24	ENST00000379802.8
DSP	NM_001008844.3	c.3583-1433A>T		intron_variant
DSP	NM_001319034.2	c.4050+969A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.5019A>T	p.Glu1673Asp	missense_variant	23/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.3583-1433A>T		intron_variant		1		A2
DSP	ENST00000710359.1	c.4050+969A>T		intron_variant				A2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152244 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250882 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135802

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461842 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727224

Gnomad4 AFR exome AF: 0.000119

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74384

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

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

Jan 11, 2024

- -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 10, 2022

This missense variant replaces glutamic acid with aspartic acid at codon 1673 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 cardiovascular disorders in the literature. This variant has been identified in 1/250882 chromosomes 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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.082
Dann	Benign	0.79
DEOGEN2	Benign	0.25	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.23
Sift	Benign	0.57	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.093
MutPred		0.093		Loss of methylation at K1676 (P = 0.0794);
MVP		0.40
MPC		0.20
ClinPred		0.064	T
GERP RS		-12
Varity_R		0.038
gMVP		0.17

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: rs773113214; hg19: chr6-7581442;