6-7581514-G-T
Position:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting
The NM_004415.4(DSP):c.5324G>T(p.Arg1775Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000564 in 1,614,008 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 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000060 ( 0 hom. )
Consequence
DSP
NM_004415.4 missense
NM_004415.4 missense
Scores
12
7
Clinical Significance
Conservation
PhyloP100: 4.55
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.1629838).
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000595 (87/1461802) while in subpopulation MID AF= 0.00295 (17/5760). AF 95% confidence interval is 0.00188. There are 0 homozygotes in gnomad4_exome. There are 57 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.5324G>T | p.Arg1775Ile | missense_variant | 23/24 | ENST00000379802.8 | NP_004406.2 | |
DSP | NM_001319034.2 | c.4051-1128G>T | intron_variant | NP_001305963.1 | ||||
DSP | NM_001008844.3 | c.3583-1128G>T | intron_variant | NP_001008844.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.5324G>T | p.Arg1775Ile | missense_variant | 23/24 | 1 | NM_004415.4 | ENSP00000369129.3 | ||
DSP | ENST00000418664.2 | c.3583-1128G>T | intron_variant | 1 | ENSP00000396591.2 | |||||
DSP | ENST00000710359.1 | c.4051-1128G>T | intron_variant | ENSP00000518230.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152206Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
4
AN:
152206
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000678 AC: 17AN: 250768Hom.: 0 AF XY: 0.0000958 AC XY: 13AN XY: 135696
GnomAD3 exomes
AF:
AC:
17
AN:
250768
Hom.:
AF XY:
AC XY:
13
AN XY:
135696
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000595 AC: 87AN: 1461802Hom.: 0 Cov.: 32 AF XY: 0.0000784 AC XY: 57AN XY: 727192
GnomAD4 exome
AF:
AC:
87
AN:
1461802
Hom.:
Cov.:
32
AF XY:
AC XY:
57
AN XY:
727192
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74362
GnomAD4 genome
AF:
AC:
4
AN:
152206
Hom.:
Cov.:
32
AF XY:
AC XY:
2
AN XY:
74362
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
1
ExAC
AF:
AC:
10
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:13Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | DSP: PM2, BP4 - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 08, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 15, 2021 | Identified in one heterozygous individual with woolly hair referred for exome sequencing at GeneDx; however, no cardiac-related clinical information or informative segregation data is available; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID 161227; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26582918, 27535533, 31402444, 25637381, 28472724, 21723241, 23861362, 15941723, 23299917) - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 31, 2014 | The p.Arg1775Ile variant in DSP has been previously reported in 1 adult with sud den death and segregated with right ventricular and ECG abnormalities in 2 affec ted family members (Bauce 2005). This variant has also been identified in 8/1655 6 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs34738426). The affected amino acid is not well cons erved in evolution, raising the possibility that a change may be tolerated; howe ver, this is not predictive enough to rule out pathogenicity. In summary, the cl inical significance of the p.Arg1775Ile variant is uncertain. - |
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 09, 2024 | This missense variant replaces arginine with isoleucine at codon 1775 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in four related individuals from a family (Family 151, PMID: 15941723). Only one of these individuals, a female who was diagnosed at the age of 37 year old, was affected with ventricular fibrillation and and aborted sudden death, but she did not fulfill diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy. The proband's 13 year old son, 52 year old sister and her 18 year old son (proband's nephew) were unaffected although the proband's son had positive late potentials and sister had right ventricular abnormalities (PMID: 15941723). This variant has been identified in 18/282174 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 23, 2023 | This missense variant replaces arginine with isoleucine at codon 1775 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in four related individuals from a family (Family 151, PMID: 15941723). Only one of these individuals, a female who was diagnosed at the age of 37 year old, was affected with ventricular fibrillation and and aborted sudden death, but she did not fulfill diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy. The proband's 13 year old son, 52 year old sister and her 18 year old son (proband's nephew) were unaffected although the proband's son had positive late potentials and sister had right ventricular abnormalities (PMID: 15941723). This variant has been identified in 18/282174 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Woolly hair-skin fragility syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 25, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Arrhythmogenic right ventricular dysplasia 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 31, 2018 | This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Arrhythmogenic right ventricular dysplasia 8, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1-Supporting => BS1 downgraded in strength to supporting. - |
Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 19, 2021 | - - |
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 18, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
N
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at