rs201930322

chr6-7565470-G-Achr6-7565470-G-Cchr6-7565470-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1 PP3 BP6

The NM_004415.4(DSP):c.889G>A(p.Asp297Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D297H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:4
• Conservation: PhyloP100: 9.86

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_004415.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787
• BP6: Variant 6-7565470-G-A is Benign according to our data. Variant chr6-7565470-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44980.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.889G>A	p.Asp297Asn	missense_variant	7/24	ENST00000379802.8
DSP	NM_001319034.2	c.889G>A	p.Asp297Asn	missense_variant	7/24
DSP	NM_001008844.3	c.889G>A	p.Asp297Asn	missense_variant	7/24
DSP	NM_001406591.1	c.889G>A	p.Asp297Asn	missense_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.889G>A	p.Asp297Asn	missense_variant	7/24	1	NM_004415.4	P2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152138 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251334 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135834

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000179 AC: 261 AN: 1461814 Hom.: 0 Cov.: 31 AF XY: 0.000177 AC XY: 129 AN XY: 727216

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000213

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152138 Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6 AN XY: 74308

Gnomad4 AFR AF: 0.0000241

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: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.000125

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 21, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2021	Reported in a patient with ARVC/D who also harbored a pathogenic variant in the PKP2 gene (Tan et al., 2010); Also reported in a patient with dilated cardiomyopathy; however, this variant was also reported in two control individuals from this study (Mazzarotto et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 44980; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31983221, 20857253) -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 24, 2016	p.Asp297Asn (c.889G>A) in the DSP gene (NM_004415.2) Seen in a patient with unexplained cardiac arrest and family history of sudden death and early-onset atrial fibrillation. Testing done by Invitae. Given its presence in controls and lack of case data, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Per our searches and the lab report, there is no case data available for this variant. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The aspartic acid at codon 297 is conserved across species. This variant is present in 10 of 60,683 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of October 2016). Specifically this variant was observed in 8 of 33340 individuals of European (non-Finnish) descent, 1 of 5202 individuals of African descent and 1 of 454 individuals of “other” descent. Of note, Kapplinger et al. (2011) from Michael Ackerman’s group have reported a significant yield of rare missense variants in the ARVC genes of presumably healthy controls from various ethnicities. According to their data, 16% of 427 controls hosted missense variants—similar to the 21% yield in 175 Dutch and U.S. ARVC cases. This is a reminder that missense variants of unknown significance in ARVC-related genes need to be interpreted with caution. Kapplinger et al. also report a “hot spot” for DSP variants between amino acids 250-604 in patients with ARVC but not in controls. Furthermore, in the ExAC constraint analyses, DSP appears to be fairly tolerant to missense variation (Z=0.91), but not to loss of function/truncating variation (pLI=1.000) -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 22, 2012	The Asp297Asn variant (DSP) has been identified in 1/7020 European American chro mosomes and 1/3738 African American chromosomes from a broad population by the N HLBI Exome sequencing project (http://evs.gs.washington.edu/EVS). Aspartic acid (Asp) at position 297 is highly conserved in mammals and across evolutionarily d istant species, though computational analyses (biochemical amino acid properties , AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against a n impact to the protein. Additional information is needed to fully assess the cl inical significance of the Asp297Asn variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 11, 2021	Variant summary: DSP c.889G>A (p.Asp297Asn) results in a conservative amino acid change located in the Spectrin/alpha-actinin repeat (IPR018159) 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 6e-05 in 251334 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (6e-05 vs 0.0002), allowing no conclusion about variant significance. c.889G>A has been reported in the literature in an individual affected with Dilated cardiomyopathy but it was also reported in healthy controls (Mazzarotto_2020). This report does not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jan 05, 2024	This sequence change in DSP is predicted to replace aspartic acid with asparagine at codon 297, p.(Asp297Asn). The aspartic acid residue is highly conserved (100 vertebrates, UCSC) and is located in the globular 1 region. There is a small physicochemical difference between aspartic acid and asparagine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.012% (16/129,034 alleles) in the European (non-Finnish) population. This variant has been reported in multiple individuals with and without cardiomyopathy. (PMID: 31983221, 33874732). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.731). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 18, 2023	This missense variant replaces aspartic acid with asparagine at codon 297 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 20/282706 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. -

Conduction disorder of the heart Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Apr 16, 2019

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2022

The c.889G>A (p.D297N) alteration is located in exon 7 (coding exon 7) of the DSP gene. This alteration results from a G to A substitution at nucleotide position 889, causing the aspartic acid (D) at amino acid position 297 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

- -

Lethal acantholytic epidermolysis bullosa Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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

Apr 28, 2017

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

Apr 28, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.0099	T
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.71
MVP		0.92
MPC		0.81
ClinPred		0.86	D
GERP RS		5.5
Varity_R		0.73
gMVP		0.73

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: rs201930322; hg19: chr6-7565703; COSMIC: COSV65792536;