rs139799237

chr6-7576437-G-Achr6-7576437-G-Cchr6-7576437-G-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.2774G>A(p.Arg925Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000234 in 1,614,046 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. R925W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (3 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:6
• Conservation: PhyloP100: 4.76

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=0.06169465).
• BP6: Variant 6-7576437-G-A is Benign according to our data. Variant chr6-7576437-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 199875.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=7, Benign=1}. Variant chr6-7576437-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.2774G>A	p.Arg925Gln	missense_variant	19/24	ENST00000379802.8
DSP	NM_001319034.2	c.2774G>A	p.Arg925Gln	missense_variant	19/24
DSP	NM_001008844.3	c.2774G>A	p.Arg925Gln	missense_variant	19/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.2774G>A	p.Arg925Gln	missense_variant	19/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.2774G>A	p.Arg925Gln	missense_variant	19/24	1		A2
DSP	ENST00000710359.1	c.2774G>A	p.Arg925Gln	missense_variant	19/24			A2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152122 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000243 AC: 61 AN: 251362 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135866

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000243 AC: 355 AN: 1461806 Hom.: 3 Cov.: 34 AF XY: 0.000297 AC XY: 216 AN XY: 727204

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000614

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000211

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74444

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000238 Hom.: 0

Bravo AF: 0.000215

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000545

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	DSP: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Dec 03, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2019	This variant is associated with the following publications: (PMID: 26383259, 26743238) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 20, 2022	- -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 28, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 18, 2015

The p.Arg925Gln variant in DSP has not been previously reported in individuals w ith cardiomyopathy, but has been identified in up to 0.2% of chromosomes (13/667 32) from multiple ethnic groups curated by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org; dbSNP rs139799237). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg925Gln variant is uncertain. -

Lethal acantholytic epidermolysis bullosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Woolly hair-skin fragility syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Arrhythmogenic right ventricular dysplasia 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Familial restrictive cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Klaassen Lab, Charite University Medicine Berlin

Jul 03, 2019

- -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.86	D;T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.062	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.56	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.16	N;N
REVEL	Benign	0.058
Sift	Benign	0.17	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.38	B;.
Vest4		0.44
MVP		0.42
MPC		0.34
ClinPred		0.034	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.083
gMVP		0.21

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: rs139799237; hg19: chr6-7576670; COSMIC: COSV65791951;