chr3-120633316-CTC-TA
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000187.4(HGD):c.1017_1019delinsTA(p.Met339IlefsTer30) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
HGD
NM_000187.4 frameshift
NM_000187.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.40
Genes affected
HGD (HGNC:4892): (homogentisate 1,2-dioxygenase) This gene encodes the enzyme homogentisate 1,2 dioxygenase. This enzyme is involved in the catabolism of the amino acids tyrosine and phenylalanine. Mutations in this gene are the cause of the autosomal recessive metabolism disorder alkaptonuria.[provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 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. There are 58 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-120633316-CTC-TA is Pathogenic according to our data. Variant chr3-120633316-CTC-TA is described in ClinVar as [Pathogenic]. Clinvar id is 371197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HGD | NM_000187.4 | c.1017_1019delinsTA | p.Met339IlefsTer30 | frameshift_variant | 13/14 | ENST00000283871.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HGD | ENST00000283871.10 | c.1017_1019delinsTA | p.Met339IlefsTer30 | frameshift_variant | 13/14 | 1 | NM_000187.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Alkaptonuria Pathogenic:3
Pathogenic, no assertion criteria provided | research | Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences | - | The variant was originally described in AKU patient in PMID:19862842. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00092). - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 22, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 06, 2022 | - - |
HGD-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 23, 2023 | The HGD c.1017_1019delinsTA variant is predicted to result in a frameshift and premature protein termination (p.Met339Ilefs*30). This variant was reported in the compound heterozygous state in an individual with alkaptonuria (Vilboux et al. 2009. PubMed ID: 19862842). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in HGD are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at