rs969373062

chr6-7558264-G-Achr6-7558264-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004415.4(DSP):c.422G>A(p.Arg141Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,461,430 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R141S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DSP NM_004415.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.97

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.422G>A	p.Arg141Lys	missense_variant, splice_region_variant	3/24	ENST00000379802.8
DSP	NM_001319034.2	c.422G>A	p.Arg141Lys	missense_variant, splice_region_variant	3/24
DSP	NM_001008844.3	c.422G>A	p.Arg141Lys	missense_variant, splice_region_variant	3/24
DSP	NM_001406591.1	c.422G>A	p.Arg141Lys	missense_variant, splice_region_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.422G>A	p.Arg141Lys	missense_variant, splice_region_variant	3/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.422G>A	p.Arg141Lys	missense_variant, splice_region_variant	3/24	1		A2
DSP	ENST00000710359.1	c.422G>A	p.Arg141Lys	missense_variant, splice_region_variant	3/24			A2
DSP	ENST00000683563.1	n.314G>A		splice_region_variant, non_coding_transcript_exon_variant	3/4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461430 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726994

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with DSP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 141 of the DSP protein (p.Arg141Lys). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	26
Dann	Uncertain	0.98
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.20	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.18
Sift	Benign	0.18	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.012	B;.
Vest4		0.63
MutPred		0.37		Gain of ubiquitination at R141 (P = 0.0185);Gain of ubiquitination at R141 (P = 0.0185);
MVP		0.88
MPC		0.22
ClinPred		0.66	D
GERP RS		5.8
Varity_R		0.22
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.65		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs969373062; hg19: chr6-7558497;