rs397516916

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_004415.4(DSP):c.1274G>A(p.Arg425Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000322 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 6.64

Variant links:

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 links:

DSP (HGNC:):

DSP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27805552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4 linkuse as main transcript	c.1274G>A	p.Arg425Gln	missense_variant	11/24	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 linkuse as main transcript	c.1274G>A	p.Arg425Gln	missense_variant	11/24		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 linkuse as main transcript	c.1274G>A	p.Arg425Gln	missense_variant	11/24		NP_001008844.1	P15924-2B4DKX6Q4LE79
DSP	NM_001406591.1 linkuse as main transcript	c.1274G>A	p.Arg425Gln	missense_variant	11/11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.1274G>A	p.Arg425Gln	missense_variant	11/24	1	NM_004415.4	ENSP00000369129.3	P15924-1
DSP	ENST00000418664.2 linkuse as main transcript	c.1274G>A	p.Arg425Gln	missense_variant	11/24	1		ENSP00000396591.2	P15924-2
DSP	ENST00000710359.1 linkuse as main transcript	c.1274G>A	p.Arg425Gln	missense_variant	11/24			ENSP00000518230.1
DSP	ENST00000682228.1 linkuse as main transcript	n.1459G>A		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251266

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1461754

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727174

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 05, 2012

The Arg425Gln variant in DSP has not been reported in the literature nor previou sly identified by our laboratory. This variant has also not been identified in l arge and broad European American and African American populations by the NHLBI E xome Sequencing Project (http://evs.gs.washington.edu/EVS). Computational analys es (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and S IFT) do not provide strong support for or against an impact to the protein. Addi tional information is needed to fully assess the clinical significance of the Ar g425Gln variant. -

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

May 14, 2024

This missense variant replaces arginine with glutamine at codon 425 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 6/251266 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. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 12, 2022

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 13, 2023

Identified in a patient with LVNC in published literature (PMID: 33500567); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33500567) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2015

The c.1274G>A (p.R425Q) alteration is located in exon 11 (coding exon 11) of the DSP gene. This alteration results from a G to A substitution at nucleotide position 1274, causing the arginine (R) at amino acid position 425 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 20, 2021

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.071

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.043

MetaRNN

Benign

0.28

T;T

MetaSVM

Uncertain

0.081

MutationAssessor

Benign

1.5

L;L

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.5

N;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.016

D;D

Sift4G

Benign

0.088

T;T

Polyphen

0.78

P;.

Vest4

0.60

MutPred

0.25

Loss of ubiquitination at K423 (P = 0.0578);Loss of ubiquitination at K423 (P = 0.0578);

MVP

0.77

MPC

0.30

ClinPred

0.21

GERP RS

5.9

Varity_R

0.45

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over