chr2-42788564-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_012205.3(HAAO):c.124A>T(p.Thr42Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,592,424 control chromosomes in the GnomAD database, including 54,894 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.26 ( 5474 hom., cov: 34)

Exomes 𝑓: 0.25 ( 49420 hom. )

Consequence

HAAO
NM_012205.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.10

Publications

33 publications found

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 Gene-Disease associations (from GenCC):

vertebral, cardiac, renal, and limb defects syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
congenital vertebral-cardiac-renal anomalies syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HAAO links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.2942505E-4).

BP6

Variant 2-42788564-T-A is Benign according to our data. Variant chr2-42788564-T-A is described in ClinVar as Benign. ClinVar VariationId is 1285321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAAO	NM_012205.3 link	c.124A>T	p.Thr42Ser	missense_variant	Exon 2 of 10	ENST00000294973.11	NP_036337.2	P46952-1
HAAO	XM_011532729.4 link	c.124A>T	p.Thr42Ser	missense_variant	Exon 2 of 9		XP_011531031.1
HAAO	XM_011532730.4 link	c.22A>T	p.Thr8Ser	missense_variant	Exon 3 of 11		XP_011531032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAAO	ENST00000294973.11 link	c.124A>T	p.Thr42Ser	missense_variant	Exon 2 of 10	1	NM_012205.3	ENSP00000294973.6		P46952-1

Frequencies

GnomAD3 genomes

AF:

0.256

AC:

38870

AN:

152052

Hom.:

5473

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.114

Gnomad AMR

AF:

0.249

Gnomad ASJ

AF:

0.294

Gnomad EAS

AF:

0.597

Gnomad SAS

AF:

0.298

Gnomad FIN

AF:

0.352

Gnomad MID

AF:

0.361

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.271

GnomAD2 exomes

AF:

0.289

AC:

72608

AN:

251446

AF XY:

0.288

show subpopulations

Gnomad AFR exome

AF:

0.219

Gnomad AMR exome

AF:

0.279

Gnomad ASJ exome

AF:

0.297

Gnomad EAS exome

AF:

0.590

Gnomad FIN exome

AF:

0.347

Gnomad NFE exome

AF:

0.240

Gnomad OTH exome

AF:

0.275

GnomAD4 exome

AF:

0.248

AC:

357795

AN:

1440254

Hom.:

49420

Cov.:

AF XY:

0.250

AC XY:

179650

AN XY:

717764

show subpopulations

African (AFR)

AF:

0.215

AC:

7125

AN:

33100

American (AMR)

AF:

0.273

AC:

12214

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.294

AC:

7654

AN:

25996

East Asian (EAS)

AF:

0.619

AC:

24427

AN:

39484

South Asian (SAS)

AF:

0.291

AC:

24903

AN:

85706

European-Finnish (FIN)

AF:

0.332

AC:

17732

AN:

53390

Middle Eastern (MID)

AF:

0.312

AC:

1783

AN:

5722

European-Non Finnish (NFE)

AF:

0.226

AC:

246598

AN:

1092544

Other (OTH)

AF:

0.258

AC:

15359

AN:

59620

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

12363

24725

37088

49450

61813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8442

16884

25326

33768

42210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.256

AC:

38887

AN:

152170

Hom.:

5474

Cov.:

AF XY:

0.259

AC XY:

19293

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.212

AC:

8786

AN:

41516

American (AMR)

AF:

0.249

AC:

3817

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.294

AC:

1022

AN:

3472

East Asian (EAS)

AF:

0.597

AC:

3087

AN:

5172

South Asian (SAS)

AF:

0.298

AC:

1439

AN:

4822

European-Finnish (FIN)

AF:

0.352

AC:

3719

AN:

10576

Middle Eastern (MID)

AF:

0.350

AC:

103

AN:

294

European-Non Finnish (NFE)

AF:

0.239

AC:

16233

AN:

67992

Other (OTH)

AF:

0.274

AC:

577

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1485

2971

4456

5942

7427

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

410

820

1230

1640

2050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.243

Hom.:

3272

Bravo

AF:

0.250

TwinsUK

AF:

0.227

AC:

840

ALSPAC

AF:

0.233

AC:

899

ESP6500AA

AF:

0.225

AC:

991

ESP6500EA

AF:

0.233

AC:

2005

ExAC

AF:

0.284

AC:

34541

Asia WGS

AF:

0.432

AC:

1502

AN:

3478

EpiCase

AF:

0.244

EpiControl

AF:

0.248

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Vertebral, cardiac, renal, and limb defects syndrome 1

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.018

T;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.70

T;D

MetaRNN

Benign

0.00063

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.13

N;.

PhyloP100

1.1

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.39

N;N

REVEL

Benign

0.066

Sift

Benign

0.73

T;T

Sift4G

Benign

0.74

T;.

Polyphen

0.0010

B;.

Vest4

0.077

MutPred

0.32

Loss of phosphorylation at T42 (P = 0.0449);.;

MPC

0.054

ClinPred

0.0028

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.43

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over