6-7559225-G-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_004415.4(DSP):c.423-1G>T variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.02

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 Pathogenic. Variant got 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 8.2, offset of 10, new splice context is: ttctttgcatgcttcttcAGctc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• 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.
• PP5: Variant 6-7559225-G-T is Pathogenic according to our data. Variant chr6-7559225-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 432430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.423-1G>T		splice_acceptor_variant		ENST00000379802.8
DSP	NM_001008844.3	c.423-1G>T		splice_acceptor_variant
DSP	NM_001319034.2	c.423-1G>T		splice_acceptor_variant
DSP	NM_001406591.1	c.423-1G>T		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.423-1G>T		splice_acceptor_variant		1	NM_004415.4	P2
DSP	ENST00000418664.2	c.423-1G>T		splice_acceptor_variant		1		A2
DSP	ENST00000710359.1	c.423-1G>T		splice_acceptor_variant				A2
DSP	ENST00000683563.1	n.315-1G>T		splice_acceptor_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 13, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been observed in individual(s) with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 15941723). ClinVar contains an entry for this variant (Variation ID: 432430). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 3 of the DSP gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 30, 2017

Although the c.423-1 G>T variant has not been reported as a pathogenic or benign to our knowledge, functional studies show that a variant at the same nucleotide position, c.423-1 G>A, leads to aberrant spliced mRNA products that lead to a truncated protein (Bauce et al., 2005). Additionally, this nucleotide substitution occurs at a position that is conserved across species. The c.423-1 G>T variant destroys the canonical splice acceptor site in intron 3 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site variants in the DSP gene have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014). Furthermore, the c.423-1 G>T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2016

The c.423-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 4 of the DSP gene. This alteration has not been reported in the literature to date; however, an alteration involving the same nucleotide position, c.423-1G>A, has been reported in a family with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) and sudden death. The authors indicated RNA sequencing showed skipping of exon 4, which was predicted to result in a truncated or absent protein (Bauce B et al. Eur Heart J. 2005;26(16):1666-75). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.88		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1304410089; hg19: chr6-7559458; COSMIC: COSV65796167; COSMIC: COSV65796167;