2-42783366-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_012205.3(HAAO):c.298G>A(p.Val100Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: HAAO NM_012205.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.419

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39831886).
• BP6: Variant 2-42783366-C-T is Benign according to our data. Variant chr2-42783366-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2331610.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAAO	NM_012205.3	c.298G>A	p.Val100Met	missense_variant	4/10	ENST00000294973.11
HAAO	XM_011532729.4	c.298G>A	p.Val100Met	missense_variant	4/9
HAAO	XM_011532730.4	c.196G>A	p.Val66Met	missense_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAAO	ENST00000294973.11	c.298G>A	p.Val100Met	missense_variant	4/10	1	NM_012205.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 249264 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135056

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461176 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 726864

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	13
Dann	Uncertain	1.0
DEOGEN2	Benign	0.050	T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	0.87	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.096
Sift	Benign	0.23	T;T
Sift4G	Benign	0.11	T;.
Polyphen		0.85	P;.
Vest4		0.27
MutPred		0.70		Loss of sheet (P = 0.1398);.;
MVP		0.36
MPC		0.082
ClinPred		0.26	T
GERP RS		0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.59

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: rs759103777; hg19: chr2-43010506; COSMIC: COSV54313194;