Variant 2-42769819-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012205.3(HAAO):c.524G>C(p.Arg175Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

HAAO
NM_012205.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.49

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]

HAAO links:

HAAO (HGNC:):

HAAO links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24115822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAAO	NM_012205.3 linkuse as main transcript	c.524G>C	p.Arg175Pro	missense_variant	7/10	ENST00000294973.11	NP_036337.2	P46952-1
HAAO	XM_011532729.4 linkuse as main transcript	c.434G>C	p.Arg145Pro	missense_variant	6/9		XP_011531031.1
HAAO	XM_011532730.4 linkuse as main transcript	c.422G>C	p.Arg141Pro	missense_variant	8/11		XP_011531032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAAO	ENST00000294973.11 linkuse as main transcript	c.524G>C	p.Arg175Pro	missense_variant	7/10	1	NM_012205.3	ENSP00000294973.6		P46952-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250658

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135454

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000706

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1461474

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727034

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000850

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Vertebral, cardiac, renal, and limb defects syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jul 25, 2022

This variant was identified as compound heterozygous with NM_012205.3:c.431T>C._x000D_ Criteria applied: PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.055

T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.8

D;D

REVEL

Benign

0.16

Sift

Benign

0.22

T;T

Sift4G

Benign

0.26

T;.

Polyphen

1.0

D;.

Vest4

0.55

MutPred

0.18

Gain of glycosylation at S173 (P = 0.037);.;

MVP

0.63

MPC

0.089

ClinPred

0.74

GERP RS

5.3

Varity_R

0.85

gMVP

0.69

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over