6-7581514-G-T

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

Scores

12
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13B:1

Conservation

PhyloP100: 4.55
Variant links:
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
DSPNM_004415.4 linkc.5324G>T p.Arg1775Ile missense_variant 23/24 ENST00000379802.8 NP_004406.2 P15924-1B4DKX6
DSPNM_001319034.2 linkc.4051-1128G>T intron_variant NP_001305963.1 P15924-3B4DKX6
DSPNM_001008844.3 linkc.3583-1128G>T intron_variant NP_001008844.1 P15924-2B4DKX6Q4LE79

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DSPENST00000379802.8 linkc.5324G>T p.Arg1775Ile missense_variant 23/241 NM_004415.4 ENSP00000369129.3 P15924-1
DSPENST00000418664.2 linkc.3583-1128G>T intron_variant 1 ENSP00000396591.2 P15924-2
DSPENST00000710359.1 linkc.4051-1128G>T intron_variant ENSP00000518230.1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152206
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000678
AC:
17
AN:
250768
Hom.:
0
AF XY:
0.0000958
AC XY:
13
AN XY:
135696
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000654
GnomAD4 exome
AF:
0.0000595
AC:
87
AN:
1461802
Hom.:
0
Cov.:
32
AF XY:
0.0000784
AC XY:
57
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000302
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000306
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152206
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000678
Hom.:
0
Bravo
AF:
0.00000756
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000824
AC:
10
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

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 submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2023DSP: PM2, BP4 -
Uncertain significance, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicSep 08, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 15, 2021Identified 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 providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Arrhythmogenic right ventricular cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Uncertain significance, no assertion criteria providedresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 31, 2014The 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 submitterclinical testingAll of Us Research Program, National Institutes of HealthMay 09, 2024This 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 submitterclinical testingColor Diagnostics, LLC DBA Color HealthFeb 23, 2023This 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 submitterclinical testingBaylor GeneticsOct 25, 2019This 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 submittercurationSIB Swiss Institute of BioinformaticsMay 31, 2018This 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 19, 2021- -
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 18, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.044
T
BayesDel_noAF
Uncertain
0.010
CADD
Uncertain
25
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.49
T
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.96
D
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.16
T
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
0.55
N
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-4.0
D
REVEL
Uncertain
0.49
Sift
Uncertain
0.0050
D
Sift4G
Uncertain
0.015
D
Polyphen
0.93
P
Vest4
0.43
MVP
0.90
MPC
0.68
ClinPred
0.21
T
GERP RS
5.2
Varity_R
0.22
gMVP
0.31

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34738426; hg19: chr6-7581747; API