rs767159114
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000187.4(HGD):āc.1201G>Cā(p.Glu401Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,772 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 Likely pathogenic (ā ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000014 ( 0 hom. )
Consequence
HGD
NM_000187.4 missense
NM_000187.4 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 7.36
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 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant 3-120628517-C-G is Pathogenic according to our data. Variant chr3-120628517-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-120628517-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HGD | NM_000187.4 | c.1201G>C | p.Glu401Gln | missense_variant | 14/14 | ENST00000283871.10 | NP_000178.2 | |
HGD | XM_005247412.3 | c.976G>C | p.Glu326Gln | missense_variant | 12/12 | XP_005247469.1 | ||
HGD | XM_017006277.3 | c.778G>C | p.Glu260Gln | missense_variant | 14/14 | XP_016861766.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HGD | ENST00000283871.10 | c.1201G>C | p.Glu401Gln | missense_variant | 14/14 | 1 | NM_000187.4 | ENSP00000283871 | P1 | |
HGD | ENST00000492108.5 | c.*183G>C | 3_prime_UTR_variant, NMD_transcript_variant | 6/6 | 2 | ENSP00000419838 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249246Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134834
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461772Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727196
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
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:14978662. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00102). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 05, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 18, 2021 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with alkaptonuria (PMID: 14978662, 25804398, 19862842). ClinVar contains an entry for this variant (Variation ID: 371502). This variant is present in population databases (rs767159114, ExAC 0.001%). This sequence change replaces glutamic acid with glutamine at codon 401 of the HGD protein (p.Glu401Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of MoRF binding (P = 0.0509);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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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