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GeneBe

2-42783363-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_012205.3(HAAO):c.301G>T(p.Gly101Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

HAAO
NM_012205.3 missense

Scores

11
6
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 5.73
Variant links:
Genes affected
HAAO (HGNC:4796): (3-hydroxyanthranilate 3,4-dioxygenase) 3-Hydroxyanthranilate 3,4-dioxygenase is a monomeric cytosolic protein belonging to the family of intramolecular dioxygenases containing nonheme ferrous iron. It is widely distributed in peripheral organs, such as liver and kidney, and is also present in low amounts in the central nervous system. HAAO catalyzes the synthesis of quinolinic acid (QUIN) from 3-hydroxyanthranilic acid. QUIN is an excitotoxin whose toxicity is mediated by its ability to activate glutamate N-methyl-D-aspartate receptors. Increased cerebral levels of QUIN may participate in the pathogenesis of neurologic and inflammatory disorders. HAAO has been suggested to play a role in disorders associated with altered tissue levels of QUIN. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.978
PP5
Variant 2-42783363-C-A is Pathogenic according to our data. Variant chr2-42783363-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 988087.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HAAONM_012205.3 linkuse as main transcriptc.301G>T p.Gly101Trp missense_variant 4/10 ENST00000294973.11
HAAOXM_011532729.4 linkuse as main transcriptc.301G>T p.Gly101Trp missense_variant 4/9
HAAOXM_011532730.4 linkuse as main transcriptc.199G>T p.Gly67Trp missense_variant 5/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HAAOENST00000294973.11 linkuse as main transcriptc.301G>T p.Gly101Trp missense_variant 4/101 NM_012205.3 P1P46952-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxNov 24, 2021Observed with a likely pathogenic variant on the opposite allele (in trans) in an individual tested at GeneDx with HAAO-related clinical features, who is likely also included in published literature (Szot JO et al., 2021); Published functional studies demonstrate a damaging effect to enzyme function (Szot JO et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33942433) -
Congenital NAD deficiency disorder Pathogenic:1
Pathogenic, no assertion criteria providedresearchEmbryology Laboratory, Victor Chang Cardiac Research InstituteNov 11, 2020This variant, c.301G>T, was found in compound heterozygosity with the pathogenic variant c.323G>A -
Vertebral, cardiac, renal, and limb defects syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 15, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.86
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.25
Cadd
Pathogenic
29
Dann
Uncertain
1.0
DEOGEN2
Benign
0.29
T;.
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Uncertain
0.056
D
MutationAssessor
Pathogenic
3.9
H;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-7.3
D;D
REVEL
Pathogenic
0.71
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;.
Vest4
0.92
MutPred
0.92
Gain of MoRF binding (P = 0.0399);.;
MVP
0.86
MPC
0.40
ClinPred
1.0
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.95
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-43010503; API