6-104730377-A-AC
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_020771.4(HACE1):c.2552dupG(p.Gly852TrpfsTer33) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,597,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
HACE1
NM_020771.4 frameshift
NM_020771.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.46
Genes affected
HACE1 (HGNC:21033): (HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1) This gene encodes a HECT domain and ankyrin repeat-containing ubiquitin ligase. The encoded protein is involved in specific tagging of target proteins, leading to their subcellular localization or proteasomal degradation. The protein is a potential tumor suppressor and is involved in the pathophysiology of several tumors, including Wilm's tumor. [provided by RefSeq, Mar 2016]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0652 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-104730377-A-AC is Pathogenic according to our data. Variant chr6-104730377-A-AC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1331677.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152118Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251290Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135808
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GnomAD4 exome AF: 0.0000180 AC: 26AN: 1444950Hom.: 0 Cov.: 26 AF XY: 0.0000194 AC XY: 14AN XY: 720132
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74298
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Feb 01, 2021 | PVS1, PM2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 20, 2023 | This sequence change creates a premature translational stop signal (p.Gly852Trpfs*33) in the HACE1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 58 amino acid(s) of the HACE1 protein. This variant is present in population databases (rs745394044, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with HACE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1331677). 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
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at