rs1060500615

Variant names:

• chr6-7577834-T-A
• rs1060500615
• NM_004415.4:c.2933T>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_004415.4(DSP):​c.2933T>A​(p.Ile978Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 5.95

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 -1 ACMG points.

• BP6: Variant 6-7577834-T-A is Benign according to our data. Variant chr6-7577834-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 405241.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.2933T>A	p.Ile978Lys	missense_variant	Exon 21 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.2933T>A	p.Ile978Lys	missense_variant	Exon 21 of 24		NP_001305963.1
DSP	NM_001008844.3	c.2933T>A	p.Ile978Lys	missense_variant	Exon 21 of 24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.2933T>A	p.Ile978Lys	missense_variant	Exon 21 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.2933T>A	p.Ile978Lys	missense_variant	Exon 21 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.2933T>A	p.Ile978Lys	missense_variant	Exon 21 of 24			ENSP00000518230.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251460 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135892

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: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727236

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: 0.00000629

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Nov 10, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

p.Ile978Lys (c.2933T>A) in the DSP gene (NM_004415.2) The lab classifies this variant as a variant of unknown significance. Given a lack of case data we consider this variant a variant of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been previously reported in the literature. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 0.942) and mutation taster predicts the variant to be disease causing (0.999). The lysine at codon 978 is conserved across close species, but the UCSC geneome browser reports the T at the position is not well conserved in other species suggesting there may be lack of conservation beyond the eight species reported in the mutation taster database. The nearest missense pathogenic or likely pathogenic entries into clinvar are at codons 895 987 and 1601. The variant resides at the end of the globular 1 domain of the desmoplakin domain which includes the first 1056 amino acids of the protein. Kapplinger et al., 2011 from 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 unit(s).S. ARVC cases. This is a reminder that missense variants of unknown significance in ARVC related genes need to be interpreted with cation. Kapplinger et al. Also report a "hot spot" for DSP variants between amino acids 250-604 in patients with ARVC but not in controls. In total the variant has not been seen in laboratory controls, published controls and individuals from publicly available population datasets. There are three individuals with p.Ile978Lys and two individuals with p.Ile978Val at codon 978 listed in the gnomAD dataset (http://gnomad.broadinstitute.org/). gnomAD currently includes variant calls on ~126,000 individuals of European, African, Latino and Asian descent (as of November 10, 2016). The average coverage at that site in gnomAD is around 50x. -

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy Uncertain:1

Oct 19, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces isoleucine with lysine at codon 978 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 been reported in one individual affected with dilated cardiomyopathy (PMID: 32880476). This variant has been identified in 3/251460 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. -

Cardiovascular phenotype Uncertain:1

Aug 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I978K variant (also known as c.2933T>A), located in coding exon 21 of the DSP gene, results from a T to A substitution at nucleotide position 2933. The isoleucine at codon 978 is replaced by lysine, an amino acid with dissimilar properties. This variant co-occurred with an MYH7 variant in an individual from a dilated cardiomyopathy cohort (Verdonschot JAJ et al. Circ Genom Precis Med, 2020 Oct;13:476-487). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

May 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	26
DANN	Benign	0.96
DEOGEN2	Uncertain	0.42	T;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.0	M;M
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.015	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.71
MutPred		0.46		Loss of stability (P = 0.0101);Loss of stability (P = 0.0101);
MVP		0.88
MPC		1.1
ClinPred		0.54	D
GERP RS		5.5
Varity_R		0.22
gMVP		0.59

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: rs1060500615; hg19: chr6-7578067;