Variant 6-7541916-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_004415.4(DSP):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DSP
NM_004415.4 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 3.29

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/24	ENST00000379802.8
DSP-AS1	NR_183331.1 linkuse as main transcript	n.39-863T>C		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.1A>G	p.Met1?	start_lost	1/24	1	NM_004415.4	P2	P15924-1
DSP-AS1	ENST00000690863.2 linkuse as main transcript	n.344+855T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457608

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724826

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 24, 2015

The c.1 A>G variant in the DSP gene has not been published previously, to our knowledge. As this variant changes the translation initiator Methionine codon, the resultant protein is described as p.Met1? using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine. Although no translation initiator variants have been reported in the DSP gene, many loss-of-function variants are known to be pathogenic in this gene associated with arrhythmogenic right ventricular cardiomyopathy (Stenson et al., 2014). Based on the ACMG recommendations, c.1 A>G is interpreted as a pathogenic variant. -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 02, 2023

This variant results in the loss of the translation initiation codon methionine (p.Met1?) of the DSP protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 4 individuals from a population-based cohort who had not been previously diagnosed with arrhythmogenic cardiomyopathy (PMID: 33684294). This variant has been identified in 2/233270 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While loss of DSP function is a known mechanism of disease, one cannot rule out the possibility that a downstream in-frame methionine is used for alternate translation initiation and results in the production of truncated but functional DSP protein. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 19, 2023

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2022

The p.M1? variant (also known as c.1A>G) is located in coding exon 1 of the DSP gene and results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This variant has been detected in individuals from a cohort not selected for the presence of cardiovascular disease; however, clinical details were limited (Carruth ED et al. Circ Genom Precis Med. 2019 11;12(11):e002579). Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an in-frame methionine 16 amino acids from the initiation site, which may result in N-terminal truncation of unknown functional significance. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

0.066

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Benign

-0.51

MutationTaster

Benign

0.99

D;D

PROVEAN

Benign

-0.77

N;N

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.32

B;.

Vest4

0.73

MutPred

0.99

Loss of catalytic residue at M1 (P = 0.0761);Loss of catalytic residue at M1 (P = 0.0761);

MVP

0.94

ClinPred

1.0

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.84

gMVP

0.78

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