6-7580171-C-T

Position:

chr6-7580171-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6_Very_StrongBP7

The NM_004415.4(DSP):c.3981C>T(p.Ile1327=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000756 in 1,613,796 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: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

DSP
NM_004415.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.60

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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 6-7580171-C-T is Benign according to our data. Variant chr6-7580171-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 44898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.6 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DSP	NM_004415.4 linkuse as main transcript	c.3981C>T	p.Ile1327=	synonymous_variant	23/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2 linkuse as main transcript	c.3981C>T	p.Ile1327=	synonymous_variant	23/24		NP_001305963.1
DSP	NM_001008844.3 linkuse as main transcript	c.3582+399C>T		intron_variant			NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.3981C>T	p.Ile1327=	synonymous_variant	23/24	1	NM_004415.4	ENSP00000369129	P2	P15924-1
DSP	ENST00000418664.2 linkuse as main transcript	c.3582+399C>T		intron_variant		1		ENSP00000396591	A2	P15924-2
DSP	ENST00000710359.1 linkuse as main transcript	c.3981C>T	p.Ile1327=	synonymous_variant	23/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000877

AC:

AN:

250726

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135624

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000766

AC:

112

AN:

1461802

Hom.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000863

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000658

AC:

AN:

151994

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74222

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000901

Hom.:

Bravo

AF:

0.0000264

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 21, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 21, 2023	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 31, 2017	The c.3981C>T; p.Ile1327Ile variant (rs397516934, ClinVar variant ID 44898) does not alter the amino acid sequence of the DSP protein and computational splice site prediction algorithms do not predict a change in the nearest splice site or creation of a cryptic splice site. This variant has not been reported in association with cardiomyopathy in medical literature or in gene specific variation databases. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.009% (identified on 24 out of 276,534 chromosomes). Based on the available information, the c.3981C>T variant is likely to be benign. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 19, 2012

The Ile1327Ile variant in exon 23 of DSP: This variant is not expected to have c linical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. The Ile1327Ile variant in exon 23 of DSP (allele frequency = n/a) -

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 29, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2019

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. -

DSP-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

1.6

DANN

Benign

0.85

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