rs120074173
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong
The NM_000187.4(HGD):c.1102A>G(p.Met368Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,614,126 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 Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00020 ( 0 hom. )
Consequence
HGD
NM_000187.4 missense
NM_000187.4 missense
Scores
10
8
1
Clinical Significance
Conservation
PhyloP100: 7.46
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 13 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000187.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
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MetaRNN computational evidence supports a deleterious effect, 0.83
PP5
?
Variant 3-120633233-T-C is Pathogenic according to our data. Variant chr3-120633233-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 3173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-120633233-T-C is described in Lovd as [Likely_pathogenic]. Variant chr3-120633233-T-C is described in Lovd as [Pathogenic]. Variant chr3-120633233-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HGD | NM_000187.4 | c.1102A>G | p.Met368Val | missense_variant | 13/14 | ENST00000283871.10 | |
HGD | XM_005247412.3 | c.877A>G | p.Met293Val | missense_variant | 11/12 | ||
HGD | XM_017006277.3 | c.679A>G | p.Met227Val | missense_variant | 13/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HGD | ENST00000283871.10 | c.1102A>G | p.Met368Val | missense_variant | 13/14 | 1 | NM_000187.4 | P1 | |
HGD | ENST00000470321.1 | n.442A>G | non_coding_transcript_exon_variant | 3/3 | 3 | ||||
HGD | ENST00000492108.5 | c.*84A>G | 3_prime_UTR_variant, NMD_transcript_variant | 5/6 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000335 AC: 51AN: 152134Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000167 AC: 42AN: 251288Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135798
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GnomAD4 exome AF: 0.000196 AC: 287AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.000195 AC XY: 142AN XY: 727240
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Alkaptonuria Pathogenic:8Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 368 of the HGD protein (p.Met368Val). This variant is present in population databases (rs120074173, gnomAD 0.04%). This missense change has been observed in individuals with alkaptonuria (PMID: 10340975, 19096913, 19862842). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3173). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HGD protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HGD function (PMID: 10482952). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 23, 2018 | Across a selection of the available literature, the HGD c.1102A>G (p.Met368Val) missense variant has been identified in 42 individuals with alkaptonuria, including in a homozygous state in eight individuals, in a compound heterozygous state in 32 individuals, and in a heterozygous state in three individuals (Beltrán-Valero de Bernabé et al. 1998; Beltrán-Valero de Bernabé et al. 1999a; Beltrán-Valero de Bernabé et al. 1999b; Felbor et al. 1999; Vilboux et al. 2009; Zatkova et al. 2012). The p.Met368Val variant was absent from at least 78 controls and is reported at a frequency of 0.00037 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Met368Val variant is classified as pathogenic for alkaptonuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1999 | - - |
not provided, no classification provided | literature only | GeneReviews | - | Most prevalent pathogenic variant in Europe (excluding the Slovak population) - |
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:9529363. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00097). - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Aug 25, 2015 | The c.1102A>G, p.Met368Val variant was observed to segregate with the disease in multiple affected families [Beltrán-Valero de Bernabé D et al., (1998); Vilboux T et al., (2009)]. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls [Vilboux T et al., (2009)]. The M368 residue is close to the active site of the enzyme and is located in a domain called the RmlC-like jelly roll fold. Furthermore, in an enzyme kinetics assay, this variant showed decreased activity (37% of the wild-type), reduced catalytic efficiency (14% of wild-type) and disrupted hydrophobic contacts between subunits in the trimeric assembly [RodrÃguez JM et al., (2000)]. Several computational algorithms predicted a damaging effect of this variant on the protein. The frequency of this variant is below the disease-allele frequency in the population databases [1000Genome, Exome Sequencing Project and ExAC]. In summary, the evidence meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 18, 2015 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratoire de Génétique Moléculaire, CHU Bordeaux | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 20, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10340975, 19096913, 10465119, 31980526, 31589614, 35110678, 23430897, 25681086, 32158253, 16085442, 33621656, 19862842, 30737480, 33666743, 9529363, 10594001, 10482952, 10205262, 33072517) - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Aug 19, 2022 | ACMG categories: PS1,PS4,PM2,PM3 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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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