NM_032122.5:c.1019_1020delAG
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_032122.5(DTNBP1):c.1019_1020delAG(p.Glu340GlyfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 1,614,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
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.1019_1020delAG | p.Glu340GlyfsTer7 | frameshift_variant | Exon 10 of 10 | ENST00000344537.10 | NP_115498.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152232Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000123 AC: 31AN: 251488Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135922
GnomAD4 exome AF: 0.0000650 AC: 95AN: 1461892Hom.: 0 AF XY: 0.0000715 AC XY: 52AN XY: 727246
GnomAD4 genome AF: 0.000118 AC: 18AN: 152350Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74502
ClinVar
Submissions by phenotype
not specified Uncertain:2
Variant summary: DTNBP1 c.1019_1020delAG (p.Glu340GlyfsX7) results in a premature termination codon, predicted to cause a truncation in the last exon affecting the last 12 amino acids of the encoded protein sequence, however, nonsense mediated decay is not expected to occur. The variant allele was found at a frequency of 0.00012 in 251488 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DTNBP1 causing Hermansky-Pudlak Syndrome (0.00012 vs 0.00016), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1019_1020delAG in individuals affected with Hermansky-Pudlak Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
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not provided Uncertain:2
This sequence change creates a premature translational stop signal (p.Glu340Glyfs*7) in the DTNBP1 gene. 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. This variant is present in population databases (rs752074481, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with DTNBP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 434965). 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. -
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Hermansky-Pudlak syndrome 7 Uncertain:1
This variant results in a frameshift and is predicted to result in premature termination 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 disease. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at