chr6-7571887-A-G

Position:

chr6-7571887-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The ENST00000379802.8(DSP):c.1949A>G(p.Asn650Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N650K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

DSP
ENST00000379802.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 2.53

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.058340043).

BP6

Variant 6-7571887-A-G is Benign according to our data. Variant chr6-7571887-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44869.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=3, Likely_benign=2}. Variant chr6-7571887-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DSP	NM_004415.4 linkuse as main transcript	c.1949A>G	p.Asn650Ser	missense_variant	15/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2 linkuse as main transcript	c.1949A>G	p.Asn650Ser	missense_variant	15/24		NP_001305963.1
DSP	NM_001008844.3 linkuse as main transcript	c.1949A>G	p.Asn650Ser	missense_variant	15/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.1949A>G	p.Asn650Ser	missense_variant	15/24	1	NM_004415.4	ENSP00000369129	P2	P15924-1
DSP	ENST00000418664.2 linkuse as main transcript	c.1949A>G	p.Asn650Ser	missense_variant	15/24	1		ENSP00000396591	A2	P15924-2
DSP	ENST00000710359.1 linkuse as main transcript	c.1949A>G	p.Asn650Ser	missense_variant	15/24			ENSP00000518230	A2
DSP	ENST00000684395.1 linkuse as main transcript	n.590A>G		non_coding_transcript_exon_variant	2/5

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250940

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135628

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461712

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000158

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000577

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000100

Hom.:

Bravo

AF:

0.000189

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2022	Variant summary: DSP c.1949A>G (p.Asn650Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.5e-05 in 282332 control chromosomes (gnomAD), predominantly at a frequency of 0.0004 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (0.0002), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1949A>G has been reported in the literature in individuals affected with Dilated Cardiomyopathy (van Lint_2019, Al-Shafai_2021), but these reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: two classified the variant as of uncertain significance, and one as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2013	The Asn650Ser variant in DSP has now been identified by our laboratory in 2 Blac k individuals with HCM, 1 of whom carried a pathogenic variant in another gene. This variant has also been identified in 1/4406 African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1 45650440). Computational analyses (biochemical amino acid properties, conservati on, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional information is needed to fully assess the clinical significance of this variant. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 18, 2024

Identified in patients with DCM in published literature (PMID: 30847666, 37652022, 34137518); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30847666, 37652022, 34137518, 38612618) -

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

Jan 10, 2024

- -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 02, 2019

- -

Primary dilated cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

research

Genetics and Genomics Program, Sidra Medicine

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2024

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.097

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.058

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

0.56

D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.46

N;N

REVEL

Benign

0.11

Sift

Benign

0.74

T;T

Sift4G

Benign

0.72

T;T

Polyphen

0.0020

B;.

Vest4

0.33

MVP

0.53

MPC

0.17

ClinPred

0.085

GERP RS

5.6

Varity_R

0.070

gMVP

0.099

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