rs142494121

chr6-7576386-G-Achr6-7576386-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_004415.4(DSP):c.2723G>A(p.Arg908His) variant causes a missense change. The variant allele was found at a frequency of 0.000882 in 1,614,076 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts 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. R908L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00089 (9 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:21
• Conservation: PhyloP100: 5.97

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0127342045).
• BP6: Variant 6-7576386-G-A is Benign according to our data. Variant chr6-7576386-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 177781.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=11, Benign=5, Uncertain_significance=1}. Variant chr6-7576386-G-A is described in Lovd as [Benign]. Variant chr6-7576386-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000891 (1302/1461820) while in subpopulation MID AF= 0.0215 (124/5766). AF 95% confidence interval is 0.0184. There are 9 homozygotes in gnomad4_exome. There are 684 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.2723G>A	p.Arg908His	missense_variant	19/24	ENST00000379802.8
DSP	NM_001319034.2	c.2723G>A	p.Arg908His	missense_variant	19/24
DSP	NM_001008844.3	c.2723G>A	p.Arg908His	missense_variant	19/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.2723G>A	p.Arg908His	missense_variant	19/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.2723G>A	p.Arg908His	missense_variant	19/24	1		A2
DSP	ENST00000710359.1	c.2723G>A	p.Arg908His	missense_variant	19/24			A2

Frequencies

GnomAD3 genomes AF: 0.000795 AC: 121 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00115 AC: 289 AN: 251322 Hom.: 1 AF XY: 0.00115 AC XY: 156 AN XY: 135828

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00625

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.000891 AC: 1302 AN: 1461820 Hom.: 9 Cov.: 34 AF XY: 0.000941 AC XY: 684 AN XY: 727214

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.00551

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000678

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.000795 AC: 121 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.000833 AC XY: 62 AN XY: 74436

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00133 Hom.: 4

Bravo AF: 0.00109

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00112 AC: 136

EpiCase AF: 0.00158

EpiControl AF: 0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:21

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 19, 2015	- -
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	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2023	- -
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	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DSP: BP4, BS2 -

not specified Uncertain:1 Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 08, 2018	Variant summary: DSP c.2723G>A (p.Arg908His) results in a non-conservative amino acid change located in the Spectrin/alpha-actinin domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 277668 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 107-folds higher than 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.2723G>A has been reported in the literature in individuals affected with Arrhythmia (Quarta_2011, Haas_2015, Ng_2013, Nunn_2016) including one family that showed lack of cosegregation with disease (Quarta_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign (4x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2013	Variant classified as Uncertain Significance - Favor Benign. The Arg908His varia nt in DSP has been reported in 2 individuals with ARVC, but did not segregate wi th clinical features of ARVC in 1 relative (Quarta 2011). In addition, this vari ant has now been identified by our laboratory 5 individuals with various clinica l features (1 with RCM, 1 with LVH and RV dyskinesis, 1 with ARVC, 1 with LVNC and 1 with DCM and LVNC). It has also been identified in 0.2% (13/8600) of Europ ean American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS/; dbSNP rs142494121). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide s trong support for or against an impact to the protein. In summary, the frequency of this variant and the presence in such variable phenotypes suggest that this variant is more likely benign, but additional information is needed to establish this with confidence. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:2

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Sep 04, 2023	- -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 19, 2017	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Lethal acantholytic epidermolysis bullosa Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 12, 2018

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. -

Woolly hair-skin fragility syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 12, 2018

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

Sep 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2018

This alteration is classified as 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

Oct 15, 2020

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	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.36
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.99	D;.
Vest4		0.46
MVP		0.54
MPC		0.69
ClinPred		0.054	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.53

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: rs142494121; hg19: chr6-7576619; COSMIC: COSV99059794;