rs3816182

Variant names:

• chr2-42788564-T-A
• rs3816182
• NM_012205.3:c.124A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-42788564-T-A
• chr2-42788564-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.10
• Publications: 33 publications found

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

ACMG classification

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	c.124A>T	p.Thr42Ser	missense_variant	Exon 2 of 10	ENST00000294973.11	NP_036337.2
HAAO	XM_011532729.4	c.124A>T	p.Thr42Ser	missense_variant	Exon 2 of 9		XP_011531031.1
HAAO	XM_011532730.4	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	c.124A>T	p.Thr42Ser	missense_variant	Exon 2 of 10	1	NM_012205.3	ENSP00000294973.6

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38870 AN: 152052 Hom.: 5473 Cov.: 34

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

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.: 30 AF XY: 0.250 AC XY: 179650 AN XY: 717764

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

GnomAD4 genome AF: 0.256 AC: 38887 AN: 152170 Hom.: 5474 Cov.: 34 AF XY: 0.259 AC XY: 19293 AN XY: 74386

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

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

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	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.70
DEOGEN2	Benign	0.018	T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.70	T;D
MetaRNN	Benign	0.00063	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.13	N;.
PhyloP100		1.1
PrimateAI	Benign	0.30	T
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	T
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)

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

Other links and lift over

dbSNP: rs3816182; hg19: chr2-43015704; COSMIC: COSV107324008;