NM_032122.5:c.1017_1020delAGAG
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PVS1_ModeratePM2PP5BS1_Supporting
The NM_032122.5(DTNBP1):c.1017_1020delAGAG(p.Glu340ProfsTer44) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_032122.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DTNBP1 | NM_032122.5 | c.1017_1020delAGAG | p.Glu340ProfsTer44 | frameshift_variant | Exon 10 of 10 | ENST00000344537.10 | NP_115498.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000230 AC: 35AN: 152232Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000123 AC: 31AN: 251488Hom.: 0 AF XY: 0.000132 AC XY: 18AN XY: 135922
GnomAD4 exome AF: 0.0000493 AC: 72AN: 1461892Hom.: 0 AF XY: 0.0000399 AC XY: 29AN XY: 727246
GnomAD4 genome AF: 0.000230 AC: 35AN: 152232Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23AN XY: 74374
ClinVar
Submissions by phenotype
Hermansky-Pudlak syndrome Pathogenic:1
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Hermansky-Pudlak syndrome 7 Uncertain:1
The DTNBP1 c.1017_1020delAGAG (p.Glu340ProfsTer44) variant results in a frameshift and is predicted to cause an elongation of the protein. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this Hermansky-Pudlak syndrome. -
not provided Uncertain:1
This sequence change results in a frameshift in the DTNBP1 gene (p.Glu340Profs*44). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 12 amino acid(s) of the DTNBP1 protein and extend the protein by 31 additional amino acid residues. This variant is present in population databases (rs759180894, gnomAD 0.05%). This frameshift has been observed in individual(s) with bleeding disorder and/or Hermansky-Pudlak syndrome (PMID: 31064749, 31898847). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at