rs727505037

Positions:

chr6-7580680-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004415.4(DSP):c.4490G>A(p.Arg1497Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000353 in 1,613,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1497W) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1

Conservation

PhyloP100: 6.39

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.263745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4 link	c.4490G>A	p.Arg1497Gln	missense_variant	23/24	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 link	c.4050+440G>A		intron_variant			NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 link	c.3582+908G>A		intron_variant			NP_001008844.1	P15924-2B4DKX6Q4LE79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DSP	ENST00000379802.8 link	c.4490G>A	p.Arg1497Gln	missense_variant	23/24	1	NM_004415.4	ENSP00000369129.3	P15924-1
DSP	ENST00000418664.2 link	c.3582+908G>A		intron_variant		1		ENSP00000396591.2	P15924-2
DSP	ENST00000710359.1 link	c.4050+440G>A		intron_variant				ENSP00000518230.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000722

AC:

AN:

249394

Hom.:

AF XY:

0.0000814

AC XY:

AN XY:

135054

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

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:

0.0000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000356

AC:

AN:

1461732

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 28, 2019	Variant classified as Uncertain Significance - Favor Benign. The p.Arg1497Gln variant in DSP has been identified in 1 individual with DCM. It has also been identified in 0.015% (5/33508) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain, its frequency in the general population suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Oct 31, 2016	- -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 16, 2022

This missense variant replaces arginine with glutamine at codon 1497 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 been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510) and in another individual affected with dilated cardiomyopathy (PMID: 3198322). This variant has been identified in 18/249394 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 11, 2022

Identified in patients with cardiomyopathy in the published literature (Lopes et al., 2015; Mazzarotto et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25351510, 31983221) -

Arrhythmogenic right ventricular dysplasia 8

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Jul 16, 2014

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2022

The p.R1497Q variant (also known as c.4490G>A), located in coding exon 23 of the DSP gene, results from a G to A substitution at nucleotide position 4490. The arginine at codon 1497 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a hypertrophic cardiomyopathy cohort and a dilated cardiomyopathy cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Mazzarotto F et al. Circulation, 2020 02;141:387-398). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, 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 25, 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

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.019

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.65

REVEL

Benign

0.24

Sift

Benign

0.23

Sift4G

Benign

0.22

Polyphen

0.70

Vest4

0.53

MVP

0.84

MPC

0.36

ClinPred

0.079

GERP RS

5.7

Varity_R

0.076

gMVP

0.48

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