rs794728104

Positions:

chr6-7583041-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004415.4(DSP):c.5779C>G(p.Gln1927Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 4.98

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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06748441).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4 linkuse as main transcript	c.5779C>G	p.Gln1927Glu	missense_variant	24/24	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 linkuse as main transcript	c.4450C>G	p.Gln1484Glu	missense_variant	24/24		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 linkuse as main transcript	c.3982C>G	p.Gln1328Glu	missense_variant	24/24		NP_001008844.1	P15924-2B4DKX6Q4LE79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.5779C>G	p.Gln1927Glu	missense_variant	24/24	1	NM_004415.4	ENSP00000369129.3	P15924-1
DSP	ENST00000418664.2 linkuse as main transcript	c.3982C>G	p.Gln1328Glu	missense_variant	24/24	1		ENSP00000396591.2	P15924-2
DSP	ENST00000710359.1 linkuse as main transcript	c.4450C>G	p.Gln1484Glu	missense_variant	24/24			ENSP00000518230.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

AN:

250848

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135664

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727228

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

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

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

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	Apr 08, 2015	Variant classified as Uncertain Significance - Favor Benign. The p.Gln1927Glu va riant in DSP has not been previously reported in individuals with cardiomyopathy or in large population studies. Glutamine (Gln) at position 1927 is conserved i n mammals but not in evolutionarily distant species and >10 avian species carry a glutamic acid (Glu), raising the possibility that this change may be tolerated . Additional computational prediction tools support that the p.Gln1927Glu varian t may not impact the protein, though this information is not predictive enough t o rule out pathogenicity. In summary, while the clinical significance of the p.G ln1927Glu variant is uncertain, the presence of the variant amino acid in multip le other species suggests that it is more likely to be benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2023	- -

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

Jul 20, 2024

This missense variant replaces glutamine with glutamic acid at codon 1927 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 1/250848 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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 28, 2022

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 1927 of the DSP protein (p.Gln1927Glu). This variant is present in population databases (rs794728104, gnomAD 0.0009%). 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: 199844). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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

Oct 20, 2022

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 01, 2016

A variant of uncertain significance has been identified in the DSP gene. The Q1927E variant has not been publishedas a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, it has been classifiedin ClinVar as a variant of uncertain significance by another clinical laboratory (ClinVar SCV000271735.1; Landrum etal., 2016). In addition, the Q1927E variant has previously been identified in one other unrelated individual referred forcardiomyopathy genetic testing at GeneDx who also harbored a pathogenic variant in the RAF1 gene. This variantwas not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. The Q1927E variantis a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differin some properties. This substitution occurs at a position that is conserved in mammals. However, Glutamic acid isthe wild type amino acid at this position in multiple species. Furthermore, in silico analysis is inconsistent in itspredictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The p.Q1927E variant (also known as c.5779C>G), located in coding exon 24 of the DSP gene, results from a C to G substitution at nucleotide position 5779. The glutamine at codon 1927 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.0057

MetaRNN

Benign

0.067

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.83

N;.

PrimateAI

Benign

0.42

PROVEAN

Benign

0.090

N;N

REVEL

Benign

0.099

Sift

Benign

0.61

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.093

MVP

0.31

MPC

0.24

ClinPred

0.29

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.070

gMVP

0.27

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