rs1304410089

chr6-7559225-G-Achr6-7559225-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1 PM2 PP3_Strong PP5

The NM_004415.4(DSP):c.423-1G>A 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 Lovd as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• 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 15 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.3, offset of 1, new splice context is: aaggtttttttctttgcaAGctt. 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-A is Pathogenic according to our data. Variant chr6-7559225-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.94	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;