2-42769348-G-C

Position:

• chr2-42769348-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012205.3(HAAO):​c.630+365C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.754 in 152,164 control chromosomes in the GnomAD database, including 43,622 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.75 (43622 hom., cov: 33)
• Consequence: HAAO NM_012205.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.230

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAAO	NM_012205.3	c.630+365C>G		intron_variant		ENST00000294973.11	NP_036337.2
HAAO	XM_011532729.4	c.540+365C>G		intron_variant			XP_011531031.1
HAAO	XM_011532730.4	c.528+365C>G		intron_variant			XP_011531032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAAO	ENST00000294973.11	c.630+365C>G		intron_variant		1	NM_012205.3	ENSP00000294973.6
HAAO	ENST00000402698.6	n.974+365C>G		intron_variant		5
HAAO	ENST00000404451.7	n.389+795C>G		intron_variant		3
HAAO	ENST00000406007.6	n.181+365C>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.754 AC: 114616 AN: 152046 Hom.: 43585 Cov.: 33

Gnomad AFR AF: 0.843

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.808

Gnomad ASJ AF: 0.786

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.850

Gnomad FIN AF: 0.671

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.698

Gnomad OTH AF: 0.761

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.754 AC: 114708 AN: 152164 Hom.: 43622 Cov.: 33 AF XY: 0.754 AC XY: 56038 AN XY: 74358

Gnomad4 AFR AF: 0.842

Gnomad4 AMR AF: 0.808

Gnomad4 ASJ AF: 0.786

Gnomad4 EAS AF: 0.689

Gnomad4 SAS AF: 0.850

Gnomad4 FIN AF: 0.671

Gnomad4 NFE AF: 0.698

Gnomad4 OTH AF: 0.763

Alfa AF: 0.602 Hom.: 1581

Bravo AF: 0.767

Asia WGS AF: 0.782 AC: 2717 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.6
DANN	Benign	0.77

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

Other links and lift over

dbSNP: rs4953658; hg19: chr2-42996488;