6-7541917-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_SupportingPM2
The NM_004415.4(DSP):āc.2T>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 0.0000133 in 150,002 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
Consequence
NM_004415.4 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000133 AC: 2AN: 150002Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000857 AC: 2AN: 233270Hom.: 0 AF XY: 0.00000779 AC XY: 1AN XY: 128308
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000405 AC: 59AN: 1455058Hom.: 0 Cov.: 32 AF XY: 0.0000442 AC XY: 32AN XY: 723614
GnomAD4 genome AF: 0.0000133 AC: 2AN: 150002Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 73250
ClinVar
Submissions by phenotype
not specified Uncertain:1
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Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
This variant results in the loss of the translation initiation codon methionine (p.Met1?) of the DSP gene. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy (PMID: 31317183). 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 downstream in-frame methionine (e.g., p.Met17) may be used for alternate protein translation initiation and lead to the production of functional 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. -
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
This sequence change affects the initiator methionine of the DSP mRNA. The next in-frame methionine is located at codon 17. This variant is present in population databases (rs748738880, gnomAD 0.002%). Disruption of the initiator codon has been observed in individual(s) with clinical features of DSP-related conditions (PMID: 31317183). ClinVar contains an entry for this variant (Variation ID: 429571). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Cardiomyopathy Uncertain:1
This variant results in the loss of the translation initiation codon methionine (p.Met1?) of the DSP gene. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy (PMID: 31317183). 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 may be used for alternate protein translation initiation and lead to the production of functional 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
Reported previously by whole-exome sequencing in 1 of 61,019 individuals in the DiscovEHR cohort, with no indication of cardiomyopathy from the electronic health record of that individual (Carruth et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31638835) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at