2-42769348-G-C

Variant names:

• chr2-42769348-G-C
• rs4953658
• NM_012205.3:c.630+365C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
• congenital vertebral-cardiac-renal anomalies syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012205.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAAO	NM_012205.3	MANE Select	c.630+365C>G		intron	N/A	NP_036337.2	P46952-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAAO	ENST00000294973.11	TSL:1 MANE Select	c.630+365C>G		intron	N/A	ENSP00000294973.6	P46952-1
	HAAO	ENST00000878444.1		c.630+365C>G		intron	N/A	ENSP00000548503.1
	HAAO	ENST00000878445.1		c.705+365C>G		intron	N/A	ENSP00000548504.1

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

African (AFR) AF: 0.842 AC: 34987 AN: 41530

American (AMR) AF: 0.808 AC: 12357 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.786 AC: 2726 AN: 3470

East Asian (EAS) AF: 0.689 AC: 3566 AN: 5172

South Asian (SAS) AF: 0.850 AC: 4101 AN: 4824

European-Finnish (FIN) AF: 0.671 AC: 7095 AN: 10578

Middle Eastern (MID) AF: 0.878 AC: 258 AN: 294

European-Non Finnish (NFE) AF: 0.698 AC: 47483 AN: 67992

Other (OTH) AF: 0.763 AC: 1608 AN: 2108

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.6
DANN	Benign	0.77
PhyloP100		-0.23
Mutation Taster		=100/0	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: rs4953658; hg19: chr2-42996488;