6-7567779-A-T

Variant names:

• chr6-7567779-A-T
• rs794728111
• NM_004415.4:c.1141-2A>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_004415.4(DSP):​c.1141-2A>T variant causes a splice acceptor, intron 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, intron
• 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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.014623956 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
• 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 rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.1141-2A>T		splice_acceptor_variant, intron_variant	Intron 9 of 23	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1141-2A>T		splice_acceptor_variant, intron_variant	Intron 9 of 23		NP_001305963.1
DSP	NM_001008844.3	c.1141-2A>T		splice_acceptor_variant, intron_variant	Intron 9 of 23		NP_001008844.1
DSP	NM_001406591.1	c.1141-2A>T		splice_acceptor_variant, intron_variant	Intron 9 of 10		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1141-2A>T		splice_acceptor_variant, intron_variant	Intron 9 of 23	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.1141-2A>T		splice_acceptor_variant, intron_variant	Intron 9 of 23	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.1141-2A>T		splice_acceptor_variant, intron_variant	Intron 9 of 23			ENSP00000518230.1
DSP	ENST00000682228.1	n.794A>T		non_coding_transcript_exon_variant	Exon 3 of 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

Jul 17, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 19, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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;