6-7541916-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_004415.4(DSP):ā€‹c.1A>Gā€‹(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 Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 30)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

DSP
NM_004415.4 start_lost

Scores

5
4
7

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

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

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PVS1
Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 48 CDS bases. Genomic position: 7541963. Lost 0.006 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DSPNM_004415.4 linkc.1A>G p.Met1? start_lost Exon 1 of 24 ENST00000379802.8 NP_004406.2 P15924-1B4DKX6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DSPENST00000379802.8 linkc.1A>G p.Met1? start_lost Exon 1 of 24 1 NM_004415.4 ENSP00000369129.3 P15924-1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1457608
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
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.:
30

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Nov 02, 2023
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Oct 19, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

not provided Uncertain:1
Nov 13, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Cardiovascular phenotype Uncertain:1
Nov 23, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
D
BayesDel_noAF
Uncertain
0.010
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.17
T;.
Eigen
Benign
0.066
Eigen_PC
Benign
0.14
FATHMM_MKL
Benign
0.62
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.99
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Benign
-0.51
T
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
D
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.

Other links and lift over

dbSNP: rs1131691557; hg19: chr6-7542149; API