6-7567779-A-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Very_Strong

The NM_004415.4(DSP):c.1141-2A>T variant causes a splice acceptor change involving the alteration of a conserved nucleotide. 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: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.29

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 16 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.014507893 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.9, offset of 10, new splice context is: tccttcactgttttttgaAGagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe 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 6-7567779-A-T is Pathogenic according to our data. Variant chr6-7567779-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 517383.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.1141-2A>T		splice_acceptor_variant		ENST00000379802.8
DSP	NM_001008844.3	c.1141-2A>T		splice_acceptor_variant
DSP	NM_001319034.2	c.1141-2A>T		splice_acceptor_variant
DSP	NM_001406591.1	c.1141-2A>T		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.1141-2A>T		splice_acceptor_variant		1	NM_004415.4	P2
DSP	ENST00000418664.2	c.1141-2A>T		splice_acceptor_variant		1		A2
DSP	ENST00000710359.1	c.1141-2A>T		splice_acceptor_variant				A2
DSP	ENST00000682228.1	n.794A>T		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 17, 2017

The c.1141-2A>T variant in DSP has not been previously reported in individuals w ith cardiomyopathy or in large population studies. This variant occurs in the in variant region (+/- 1,2) of the splice consensus sequence and is predicted to ca use altered splicing leading to an abnormal or absent protein, which is common a mong disease causing DSP variants. In summary, although additional studies are required to fully establish its clinical significance, the c.1141-2A>T variant i s likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 19, 2021

Has not been previously published in association with DSP-related disorders to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Reported in ClinVar as likely pathogenic (ClinVar Variant ID# 517383; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 31447099, 31638835) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	35
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 12
DS_AL_spliceai		1.0		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs794728111; hg19: chr6-7568012;