rs140488069

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_004415.4(DSP):​c.1155G>A​(p.Ala385Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000669 in 1,613,756 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

DSP
NM_004415.4 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.40
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 Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 6-7567795-G-A is Benign according to our data. Variant chr6-7567795-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 378907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-1.4 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DSPNM_004415.4 linkc.1155G>A p.Ala385Ala synonymous_variant Exon 10 of 24 ENST00000379802.8 NP_004406.2 P15924-1B4DKX6
DSPNM_001319034.2 linkc.1155G>A p.Ala385Ala synonymous_variant Exon 10 of 24 NP_001305963.1 P15924-3B4DKX6
DSPNM_001008844.3 linkc.1155G>A p.Ala385Ala synonymous_variant Exon 10 of 24 NP_001008844.1 P15924-2B4DKX6Q4LE79
DSPNM_001406591.1 linkc.1155G>A p.Ala385Ala synonymous_variant Exon 10 of 11 NP_001393520.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DSPENST00000379802.8 linkc.1155G>A p.Ala385Ala synonymous_variant Exon 10 of 24 1 NM_004415.4 ENSP00000369129.3 P15924-1
DSPENST00000418664.2 linkc.1155G>A p.Ala385Ala synonymous_variant Exon 10 of 24 1 ENSP00000396591.2 P15924-2
DSPENST00000710359.1 linkc.1155G>A p.Ala385Ala synonymous_variant Exon 10 of 24 ENSP00000518230.1
DSPENST00000682228.1 linkn.810G>A non_coding_transcript_exon_variant Exon 3 of 3

Frequencies

GnomAD3 genomes
AF:
0.0000658
AC:
10
AN:
152004
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000955
AC:
24
AN:
251194
Hom.:
0
AF XY:
0.000110
AC XY:
15
AN XY:
135770
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000326
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.000106
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000670
AC:
98
AN:
1461636
Hom.:
0
Cov.:
34
AF XY:
0.0000605
AC XY:
44
AN XY:
727126
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.000169
Gnomad4 NFE exome
AF:
0.0000675
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152120
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000991
Hom.:
0
Bravo
AF:
0.0000567
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000178

ClinVar

Significance: Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Oct 26, 2015
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 13, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Dec 18, 2023
All of Us Research Program, National Institutes of Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Jul 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiomyopathy Benign:1
Nov 30, 2018
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:1
Mar 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1
Aug 05, 2020
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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 Benign:1
Sep 14, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
CADD
Benign
5.6
DANN
Benign
0.71
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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: rs140488069; hg19: chr6-7568028; COSMIC: COSV65791209; COSMIC: COSV65791209; API