NM_004415.4:c.1267-2A>G

Variant names:

• chr6-7568435-A-G
• rs1554106830
• NM_004415.4:c.1267-2A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_004415.4(DSP):​c.1267-2A>G 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DSP NM_004415.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.95
• Publications: 1 publications found

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]

DSP Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 8

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• keratosis palmoplantaris striata 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp
• skin fragility-woolly hair-palmoplantar keratoderma syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
• arrhythmogenic cardiomyopathy with wooly hair and keratoderma

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Orphanet, Ambry Genetics
• cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• striate palmoplantar keratoderma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe dermatitis-multiple allergies-metabolic wasting syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.01775766 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6, offset of -39, new splice context is: atctcctctaaaactcacAGggt. Cryptic site results in inframe 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 6-7568435-A-G is Pathogenic according to our data. Variant chr6-7568435-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534305. Variant chr6-7568435-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534305. Variant chr6-7568435-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534305. Variant chr6-7568435-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534305. Variant chr6-7568435-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534305. Variant chr6-7568435-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534305. Variant chr6-7568435-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534305. Variant chr6-7568435-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534305. Variant chr6-7568435-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534305. Variant chr6-7568435-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534305. Variant chr6-7568435-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534305. Variant chr6-7568435-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534305.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.1267-2A>G		splice_acceptor_variant, intron_variant	Intron 10 of 23	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1267-2A>G		splice_acceptor_variant, intron_variant	Intron 10 of 23		NP_001305963.1
DSP	NM_001008844.3	c.1267-2A>G		splice_acceptor_variant, intron_variant	Intron 10 of 23		NP_001008844.1
DSP	NM_001406591.1	c.1267-2A>G		splice_acceptor_variant, intron_variant	Intron 10 of 10		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1267-2A>G		splice_acceptor_variant, intron_variant	Intron 10 of 23	1	NM_004415.4	ENSP00000369129.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

May 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 10 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of DSP-related conditions (PMID: 30453078, 31317183, 36043215). ClinVar contains an entry for this variant (Variation ID: 534305). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Cardiovascular phenotype Uncertain:1

Feb 23, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1267-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 11 in the DSP gene. This variant has been detected in an individual from an arrhythmogenic right ventricular cardiomyopathy cohort, and an individual from a dilated cardiomyopathy cohort; however, details were limited (Poloni G et al. Heart Rhythm, 2019 05;16:773-780; Augusto JB et al. Eur Heart J Cardiovasc Imaging, 2020 Mar 1;21(3):326-336). Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		8.9
GERP RS		5.9
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.53		Position offset: -37
DS_AL_spliceai		1.0		Position offset: 2

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

Other links and lift over

dbSNP: rs1554106830; hg19: chr6-7568668;