rs77445784

chr6-7542020-G-Achr6-7542020-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004415.4(DSP):c.105G>A(p.Gly35=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00785 in 1,584,904 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0058 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0081 ( 58 hom. )

Consequence

DSP
NM_004415.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -0.489

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]

DSP links:

DSP-AS1 (HGNC:56039): (DSP antisense RNA 1)

DSP-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 6-7542020-G-A is Benign according to our data. Variant chr6-7542020-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7542020-G-A is described in Lovd as [Benign]. Variant chr6-7542020-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.489 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00575 (876/152312) while in subpopulation AMR AF= 0.0106 (163/15308). AF 95% confidence interval is 0.00931. There are 4 homozygotes in gnomad4. There are 405 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4 linkuse as main transcript	c.105G>A	p.Gly35=	synonymous_variant	1/24	ENST00000379802.8
DSP-AS1	NR_183331.1 linkuse as main transcript	n.39-967C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.105G>A	p.Gly35=	synonymous_variant	1/24	1	NM_004415.4	P2	P15924-1
DSP-AS1	ENST00000690863.2 linkuse as main transcript	n.344+751C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00576

AC:

877

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00176

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00870

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00530

AC:

1010

AN:

190676

Hom.:

AF XY:

0.00528

AC XY:

546

AN XY:

103492

show subpopulations

Gnomad AFR exome

AF:

0.00211

Gnomad AMR exome

AF:

0.00493

Gnomad ASJ exome

AF:

0.00114

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000823

Gnomad FIN exome

AF:

0.00179

Gnomad NFE exome

AF:

0.00939

Gnomad OTH exome

AF:

0.00707

GnomAD4 exome

AF:

0.00807

AC:

11562

AN:

1432592

Hom.:

Cov.:

AF XY:

0.00777

AC XY:

5521

AN XY:

710218

show subpopulations

Gnomad4 AFR exome

AF:

0.00177

Gnomad4 AMR exome

AF:

0.00536

Gnomad4 ASJ exome

AF:

0.00157

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000730

Gnomad4 FIN exome

AF:

0.00257

Gnomad4 NFE exome

AF:

0.00963

Gnomad4 OTH exome

AF:

0.00763

GnomAD4 genome

AF:

0.00575

AC:

876

AN:

152312

Hom.:

Cov.:

AF XY:

0.00544

AC XY:

405

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00176

Gnomad4 AMR

AF:

0.0106

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.00870

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00558

Hom.:

Bravo

AF:

0.00645

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 04, 2017	p.Gly35Gly in exon 1 of DSP: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 1.6% (293/18358) of E uropean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs77445784). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 06, 2014	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	DSP: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 14, 2018	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 13, 2015	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Lethal acantholytic epidermolysis bullosa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Woolly hair-skin fragility syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Arrhythmogenic right ventricular dysplasia 8

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

Cadd

Benign

9.7

Dann

Benign

0.96

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over