chr6-7563726-T-G
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_004415.4(DSP):c.727-10T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,612,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
DSP
NM_004415.4 intron
NM_004415.4 intron
Scores
2
Splicing: ADA: 0.001268
2
Clinical Significance
Conservation
PhyloP100: -0.0950
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 6-7563726-T-G is Benign according to our data. Variant chr6-7563726-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44949.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr6-7563726-T-G is described in Lovd as [Likely_benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.727-10T>G | intron_variant | ENST00000379802.8 | NP_004406.2 | |||
DSP | NM_001319034.2 | c.727-10T>G | intron_variant | NP_001305963.1 | ||||
DSP | NM_001008844.3 | c.727-10T>G | intron_variant | NP_001008844.1 | ||||
DSP | NM_001406591.1 | c.727-10T>G | intron_variant | NP_001393520.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.727-10T>G | intron_variant | 1 | NM_004415.4 | ENSP00000369129.3 | ||||
DSP | ENST00000418664.2 | c.727-10T>G | intron_variant | 1 | ENSP00000396591.2 | |||||
DSP | ENST00000710359.1 | c.727-10T>G | intron_variant | ENSP00000518230.1 | ||||||
DSP | ENST00000506617.1 | n.245-10T>G | intron_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152200Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251410Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135886
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GnomAD4 exome AF: 0.0000363 AC: 53AN: 1459958Hom.: 0 Cov.: 30 AF XY: 0.0000330 AC XY: 24AN XY: 726458
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74358
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:1
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 25, 2012 | The 727-10T>G variant (DSP) has been identified in 1/7020 European American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS). This variant is located in the 3' splice region. Compu tational tools do not provide strong support for or against an impact to splicin g. Additional studies are needed to fully assess the clinical significance of th e 727-10T>G variant. - |
not provided Uncertain:1Benign:1
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 14, 2021 | Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27535533) - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 09, 2024 | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 16, 2018 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at