2-42770474-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_012205.3(HAAO):c.440+19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,508,526 control chromosomes in the GnomAD database, including 113,004 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.36 (10294 hom., cov: 31)
  • Exomes 𝑓: 0.38 (102710 hom.)
• Consequence: HAAO NM_012205.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0250

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-42770474-G-A is Benign according to our data. Variant chr2-42770474-G-A is described in ClinVar as [Benign]. Clinvar id is 1285320.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAAO	NM_012205.3	c.440+19C>T		intron_variant		ENST00000294973.11
HAAO	XM_011532729.4	c.351-288C>T		intron_variant
HAAO	XM_011532730.4	c.338+19C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAAO	ENST00000294973.11	c.440+19C>T		intron_variant		1	NM_012205.3	P1

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54472 AN: 151926 Hom.: 10292 Cov.: 31

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.642

Gnomad SAS AF: 0.442

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.379

GnomAD3 exomes AF: 0.401 AC: 58149 AN: 145054 Hom.: 12334 AF XY: 0.406 AC XY: 30795 AN XY: 75834

Gnomad AFR exome AF: 0.264

Gnomad AMR exome AF: 0.341

Gnomad ASJ exome AF: 0.431

Gnomad EAS exome AF: 0.634

Gnomad SAS exome AF: 0.438

Gnomad FIN exome AF: 0.454

Gnomad NFE exome AF: 0.370

Gnomad OTH exome AF: 0.394

GnomAD4 exome AF: 0.384 AC: 520992 AN: 1356482 Hom.: 102710 Cov.: 24 AF XY: 0.386 AC XY: 258514 AN XY: 669992

Gnomad4 AFR exome AF: 0.263

Gnomad4 AMR exome AF: 0.342

Gnomad4 ASJ exome AF: 0.432

Gnomad4 EAS exome AF: 0.654

Gnomad4 SAS exome AF: 0.438

Gnomad4 FIN exome AF: 0.438

Gnomad4 NFE exome AF: 0.372

Gnomad4 OTH exome AF: 0.384

GnomAD4 genome AF: 0.358 AC: 54477 AN: 152044 Hom.: 10294 Cov.: 31 AF XY: 0.361 AC XY: 26867 AN XY: 74332

Gnomad4 AFR AF: 0.257

Gnomad4 AMR AF: 0.341

Gnomad4 ASJ AF: 0.431

Gnomad4 EAS AF: 0.641

Gnomad4 SAS AF: 0.444

Gnomad4 FIN AF: 0.460

Gnomad4 NFE AF: 0.378

Gnomad4 OTH AF: 0.377

Alfa AF: 0.381 Hom.: 13692

Bravo AF: 0.347

Asia WGS AF: 0.519 AC: 1803 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vertebral, cardiac, renal, and limb defects syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	5.4
Dann	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2241850; hg19: chr2-42997614;