2-42767674-C-G

Position:

chr2-42767674-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_012205.3(HAAO):c.703G>C(p.Gly235Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00455 in 1,568,904 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0033 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0047 ( 14 hom. )

Consequence

HAAO
NM_012205.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 2.24

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020507514).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00327 (498/152312) while in subpopulation AMR AF= 0.00503 (77/15304). AF 95% confidence interval is 0.00428. There are 1 homozygotes in gnomad4. There are 200 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAAO	NM_012205.3 linkuse as main transcript	c.703G>C	p.Gly235Arg	missense_variant	9/10	ENST00000294973.11	NP_036337.2	P46952-1
HAAO	XM_011532729.4 linkuse as main transcript	c.613G>C	p.Gly205Arg	missense_variant	8/9		XP_011531031.1
HAAO	XM_011532730.4 linkuse as main transcript	c.601G>C	p.Gly201Arg	missense_variant	10/11		XP_011531032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HAAO	ENST00000294973.11 linkuse as main transcript	c.703G>C	p.Gly235Arg	missense_variant	9/10	1	NM_012205.3	ENSP00000294973.6	P46952-1
HAAO	ENST00000402698.6 linkuse as main transcript	n.1047G>C		non_coding_transcript_exon_variant	8/9	5
HAAO	ENST00000404451.7 linkuse as main transcript	n.644G>C		non_coding_transcript_exon_variant	6/6	3
HAAO	ENST00000406007.6 linkuse as main transcript	n.254G>C		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes

AF:

0.00327

AC:

498

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00504

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00470

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00388

AC:

694

AN:

178752

Hom.:

AF XY:

0.00405

AC XY:

387

AN XY:

95456

show subpopulations

Gnomad AFR exome

AF:

0.00102

Gnomad AMR exome

AF:

0.00614

Gnomad ASJ exome

AF:

0.00819

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000790

Gnomad FIN exome

AF:

0.000242

Gnomad NFE exome

AF:

0.00566

Gnomad OTH exome

AF:

0.00586

GnomAD4 exome

AF:

0.00469

AC:

6646

AN:

1416592

Hom.:

Cov.:

AF XY:

0.00461

AC XY:

3231

AN XY:

700914

show subpopulations

Gnomad4 AFR exome

AF:

0.000619

Gnomad4 AMR exome

AF:

0.00616

Gnomad4 ASJ exome

AF:

0.00643

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000147

Gnomad4 FIN exome

AF:

0.000574

Gnomad4 NFE exome

AF:

0.00546

Gnomad4 OTH exome

AF:

0.00413

GnomAD4 genome

AF:

0.00327

AC:

498

AN:

152312

Hom.:

Cov.:

AF XY:

0.00269

AC XY:

200

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.00503

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00470

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00529

Hom.:

Bravo

AF:

0.00401

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.000911

AC:

ESP6500EA

AF:

0.00549

AC:

ExAC

AF:

0.00259

AC:

308

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Skane University Hospital Lund

May 27, 2022

- -

HAAO-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.82

MetaRNN

Benign

0.021

MetaSVM

Uncertain

0.66

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.85

Sift

Uncertain

0.021

Sift4G

Uncertain

0.0030

Polyphen

0.93

Vest4

0.78

MVP

0.95

MPC

0.31

ClinPred

0.049

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.87

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