2-42767674-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_012205.3(HAAO):c.703G>C(p.Gly235Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00455 in 1,568,904 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (14 hom.)
• Consequence: HAAO NM_012205.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.24

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 (MetaRNN=0.020507514).
• BP6: Variant 2-42767674-C-G is Benign according to our data. Variant chr2-42767674-C-G is described in ClinVar as [Benign]. Clinvar id is 3044237.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00327 (498/152312) while in subpopulation AMR AF= 0.00503 (77/15304). AF 95% confidence interval is 0.00428. There are 1 homozygotes in gnomad4. There are 200 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAAO	NM_012205.3	c.703G>C	p.Gly235Arg	missense_variant	9/10	ENST00000294973.11
HAAO	XM_011532729.4	c.613G>C	p.Gly205Arg	missense_variant	8/9
HAAO	XM_011532730.4	c.601G>C	p.Gly201Arg	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAAO	ENST00000294973.11	c.703G>C	p.Gly235Arg	missense_variant	9/10	1	NM_012205.3	P1
HAAO	ENST00000402698.6	n.1047G>C		non_coding_transcript_exon_variant	8/9	5
HAAO	ENST00000404451.7	n.644G>C		non_coding_transcript_exon_variant	6/6	3
HAAO	ENST00000406007.6	n.254G>C		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes AF: 0.00327 AC: 498 AN: 152194 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00470

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00388 AC: 694 AN: 178752 Hom.: 4 AF XY: 0.00405 AC XY: 387 AN XY: 95456

Gnomad AFR exome AF: 0.00102

Gnomad AMR exome AF: 0.00614

Gnomad ASJ exome AF: 0.00819

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000790

Gnomad FIN exome AF: 0.000242

Gnomad NFE exome AF: 0.00566

Gnomad OTH exome AF: 0.00586

GnomAD4 exome AF: 0.00469 AC: 6646 AN: 1416592 Hom.: 14 Cov.: 31 AF XY: 0.00461 AC XY: 3231 AN XY: 700914

Gnomad4 AFR exome AF: 0.000619

Gnomad4 AMR exome AF: 0.00616

Gnomad4 ASJ exome AF: 0.00643

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000147

Gnomad4 FIN exome AF: 0.000574

Gnomad4 NFE exome AF: 0.00546

Gnomad4 OTH exome AF: 0.00413

GnomAD4 genome AF: 0.00327 AC: 498 AN: 152312 Hom.: 1 Cov.: 33 AF XY: 0.00269 AC XY: 200 AN XY: 74472

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00470

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00529 Hom.: 1

Bravo AF: 0.00401

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000911 AC: 4

ESP6500EA AF: 0.00549 AC: 47

ExAC AF: 0.00259 AC: 308

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HAAO-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.021	T
MetaSVM	Uncertain	0.66	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.93	P
Vest4		0.78
MVP		0.95
MPC		0.31
ClinPred		0.049	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.87

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: rs34053133; hg19: chr2-42994814;