6-7580562-C-G

Variant summary

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

The NM_004415.4(DSP):c.4372C>G(p.Arg1458Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00201 in 1,613,990 control chromosomes in the GnomAD database, including 4 homozygotes. 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. R1458Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (4 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:21
• Conservation: PhyloP100: 0.850

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=0.0066158175).
• BP6: Variant 6-7580562-C-G is Benign according to our data. Variant chr6-7580562-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44906.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=13, Benign=3, Uncertain_significance=5}. Variant chr6-7580562-C-G is described in Lovd as [Benign]. Variant chr6-7580562-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.4372C>G	p.Arg1458Gly	missense_variant	23/24	ENST00000379802.8
DSP	NM_001008844.3	c.3582+790C>G		intron_variant
DSP	NM_001319034.2	c.4050+322C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.4372C>G	p.Arg1458Gly	missense_variant	23/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.3582+790C>G		intron_variant		1		A2
DSP	ENST00000710359.1	c.4050+322C>G		intron_variant				A2

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 151986 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00243

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000851

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00174 AC: 437 AN: 251254 Hom.: 1 AF XY: 0.00153 AC XY: 208 AN XY: 135780

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00358

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00171

Gnomad NFE exome AF: 0.00218

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00208 AC: 3044 AN: 1461886 Hom.: 4 Cov.: 32 AF XY: 0.00198 AC XY: 1440 AN XY: 727244

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00360

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00163

Gnomad4 NFE exome AF: 0.00239

Gnomad4 OTH exome AF: 0.00204

GnomAD4 genome AF: 0.00134 AC: 204 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74354

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000851

Gnomad4 NFE AF: 0.00204

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00164 Hom.: 0

Bravo AF: 0.00162

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00173 AC: 210

EpiCase AF: 0.00262

EpiControl AF: 0.00231

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:21

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	DSP: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2020	This variant is associated with the following publications: (PMID: 21606396, 21636032, 25163546, 24503780, 25179549, 25661095, 25637381, 23299917, 23861362, 25569433, 25985138, 26332594, 27153395, 27930701, 27435932, 26743238, 24055113, 28600387, 30403697, 33232181) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -

not specified Uncertain:1 Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 07, 2017	p.Arg1458Gly in exon 23 of DSP: This variant is not expected to have clinical si gnificance because it has been identified in 0.36% (41/11544) of Latino and 0.24 % (159/66436) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs28763965). Computational prediction too ls and conservation analysis do not provide strong support for or against an imp act to the protein. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, flagged submission	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 02, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. We classify this as a variant of uncertain significance, based on the weak case data, presence of another more convincing variant in one of the cases, and the presence in control or general populations samples. The variant has been seen in at least one case of DCM and one case of ARVC. There is no segregation data available. Cox et al (2010) reported the variant in one of 149 probands with ARVC in their Dutch cohort. In the paper it appears that this is the only variant the patient had in the five desmosomal genes sequenced, however in an online database managed by one of the authors it is noted that the patient also carries a nonsense variant in DSP that they consider pathogenic. This is likely the same case included in Kapplinger et al (2011) since both are from a Dutch cohort with the same authors. Pugh et al (2014) observed the variant in one patient in a cohort of 766 patients with "DCM or clinical features consistent with DCM" who had genetic testing performed at the Lab for Molecular Medicine. The patient also carries variant of uncertain significance in TTN, CASQ2, ACTN2, and ABCC9. Both of these groups classified the variant as a variant of uncertain significance. In total the variant has been seen in 26 o f 7973 published controls and individuals from publicly available population datasets. The highest frequency is 2 of 173 individuals within the 1000 genomes dataset. The variant was reported online in 18 of 4300 Caucasian individuals and 4 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of April 22nd, 2014). Another variant at the same codon, p.Arg1458Gln, is present in 28 of 4300 Caucasian individuals and 0 of 2203 African-American individual. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). Per the GeneDx report, the variant was observed in 2 of 173 individuals in the 1000 Genomes project and those individuals are Hispanic. The ClinSeq group reported that they observed the variant in 2 of 870 individuals (Ng et al 2013). The variant was not observed in the following laboratory and published control samples: 427 individuals (Kapplinger et al 2011). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 14, 2020	Variant summary: DSP c.4372C>G (p.Arg1458Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 252108 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 173.34 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. c.4372C>G has been reported in the literature in individuals affected with Arrhythmia, DCM or HCM (Cox_2011, Kapplinger_2011, Pugh_2014, Andreasen_2013, Jaaskelainen_2019). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Co-occurrences with other pathogenic variant(s) have been reported (DSP c.3337C>T, R1113X; CASQ2 c.1090_1091insG, p.Asp364GlyfsX10 ; MYH7 c.3158G>A , p.Arg1053Gln), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as benign. -

Cardiomyopathy Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 29, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Nov 01, 2017	- -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Uncertain significance, flagged submission

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Oct 19, 2015

- -

Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1

Uncertain significance, flagged submission

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Primary familial dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

-

- -

Left ventricular noncompaction cardiomyopathy Uncertain:1

Uncertain significance, flagged submission

clinical testing

Blueprint Genetics

Jul 10, 2014

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Lethal acantholytic epidermolysis bullosa Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 24, 2019

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Mar 01, 2024

- -

Woolly hair-skin fragility syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 24, 2019

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Arrhythmogenic right ventricular dysplasia 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 24, 2019

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2018

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. -

DSP-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Pathogenic	0.17
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.029
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.52
Sift	Benign	0.17	T
Sift4G	Benign	0.36	T
Polyphen		0.47	P
Vest4		0.47
MVP		0.99
MPC		0.30
ClinPred		0.016	T
GERP RS		4.8
Varity_R		0.13
gMVP		0.36

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: rs28763965; hg19: chr6-7580795;