2-42769726-G-A

Position:

• chr2-42769726-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012205.3(HAAO):​c.617C>T​(p.Thr206Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HAAO NM_012205.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.763

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15703353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAAO	NM_012205.3	c.617C>T	p.Thr206Ile	missense_variant	7/10	ENST00000294973.11	NP_036337.2
HAAO	XM_011532729.4	c.527C>T	p.Thr176Ile	missense_variant	6/9		XP_011531031.1
HAAO	XM_011532730.4	c.515C>T	p.Thr172Ile	missense_variant	8/11		XP_011531032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAAO	ENST00000294973.11	c.617C>T	p.Thr206Ile	missense_variant	7/10	1	NM_012205.3	ENSP00000294973.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2024

The c.617C>T (p.T206I) alteration is located in exon 7 (coding exon 7) of the HAAO gene. This alteration results from a C to T substitution at nucleotide position 617, causing the threonine (T) at amino acid position 206 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0066	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	D;N
REVEL	Benign	0.090
Sift	Benign	0.18	T;T
Sift4G	Benign	0.19	T;.
Polyphen		0.018	B;.
Vest4		0.41
MutPred		0.30		Gain of catalytic residue at T206 (P = 0.0453);.;
MVP		0.41
MPC		0.063
ClinPred		0.15	T
GERP RS		-0.11
Varity_R		0.21
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-42996866;