6-7555830-C-T

Position:

chr6-7555830-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004415.4(DSP):c.273+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0329 in 1,612,588 control chromosomes in the GnomAD database, including 1,038 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 61 hom., cov: 33)

Exomes 𝑓: 0.034 ( 977 hom. )

Consequence

DSP
NM_004415.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.558

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 6-7555830-C-T is Benign according to our data. Variant chr6-7555830-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 44879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7555830-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.024 (3664/152350) while in subpopulation NFE AF= 0.0376 (2557/68034). AF 95% confidence interval is 0.0364. There are 61 homozygotes in gnomad4. There are 1647 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 61 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
DSP	NM_004415.4 linkuse as main transcript	c.273+10C>T	intron_variant	ENST00000379802.8	NP_004406.2
DSP	NM_001008844.3 linkuse as main transcript	c.273+10C>T	intron_variant		NP_001008844.1
DSP	NM_001319034.2 linkuse as main transcript	c.273+10C>T	intron_variant		NP_001305963.1
DSP	NM_001406591.1 linkuse as main transcript	c.273+10C>T	intron_variant		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.273+10C>T		intron_variant		1	NM_004415.4	ENSP00000369129	P2	P15924-1

Frequencies

GnomAD3 genomes

AF:

0.0241

AC:

3665

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00644

Gnomad AMI

AF:

0.0669

Gnomad AMR

AF:

0.0306

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00849

Gnomad FIN

AF:

0.0139

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0376

Gnomad OTH

AF:

0.0306

GnomAD3 exomes

AF:

0.0235

AC:

5851

AN:

249090

Hom.:

101

AF XY:

0.0237

AC XY:

3188

AN XY:

134764

show subpopulations

Gnomad AFR exome

AF:

0.00566

Gnomad AMR exome

AF:

0.0210

Gnomad ASJ exome

AF:

0.0148

Gnomad EAS exome

AF:

0.0000548

Gnomad SAS exome

AF:

0.00827

Gnomad FIN exome

AF:

0.0128

Gnomad NFE exome

AF:

0.0371

Gnomad OTH exome

AF:

0.0310

GnomAD4 exome

AF:

0.0338

AC:

49415

AN:

1460238

Hom.:

977

Cov.:

AF XY:

0.0333

AC XY:

24190

AN XY:

726392

show subpopulations

Gnomad4 AFR exome

AF:

0.00548

Gnomad4 AMR exome

AF:

0.0223

Gnomad4 ASJ exome

AF:

0.0147

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.00875

Gnomad4 FIN exome

AF:

0.0144

Gnomad4 NFE exome

AF:

0.0400

Gnomad4 OTH exome

AF:

0.0287

GnomAD4 genome

AF:

0.0240

AC:

3664

AN:

152350

Hom.:

Cov.:

AF XY:

0.0221

AC XY:

1647

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00642

Gnomad4 AMR

AF:

0.0305

Gnomad4 ASJ

AF:

0.0147

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00850

Gnomad4 FIN

AF:

0.0139

Gnomad4 NFE

AF:

0.0376

Gnomad4 OTH

AF:

0.0302

Alfa

AF:

0.0282

Hom.:

Bravo

AF:

0.0249

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 12, 2011	273+10C>T in intron 2 of DSP: This variant is not expected to have clinical sign ificance because it is not located in the conserved region of the splicing conse nsus sequence. 273+10C>T in intron 2 of DSP (allele frequency = 1.4%, 30/2000) -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 30, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiomyopathy

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Oct 04, 2022

- -

Lethal acantholytic epidermolysis bullosa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 13, 2018

Arrhythmogenic right ventricular dysplasia 8

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

6.5

DANN

Benign

0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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