2-42767918-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_012205.3(HAAO):c.641A>G(p.Tyr214Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,613,784 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (8 hom.)
• Consequence: HAAO NM_012205.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.755

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00842163).
• BP6: Variant 2-42767918-T-C is Benign according to our data. Variant chr2-42767918-T-C is described in ClinVar as [Benign]. Clinvar id is 3037735.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00234 (356/152348) while in subpopulation NFE AF= 0.00275 (187/68026). AF 95% confidence interval is 0.00243. There are 0 homozygotes in gnomad4. There are 184 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAAO	NM_012205.3	c.641A>G	p.Tyr214Cys	missense_variant	8/10	ENST00000294973.11
HAAO	XM_011532729.4	c.551A>G	p.Tyr184Cys	missense_variant	7/9
HAAO	XM_011532730.4	c.539A>G	p.Tyr180Cys	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAAO	ENST00000294973.11	c.641A>G	p.Tyr214Cys	missense_variant	8/10	1	NM_012205.3	P1
HAAO	ENST00000402698.6	n.985A>G		non_coding_transcript_exon_variant	7/9	5
HAAO	ENST00000404451.7	n.400A>G		non_coding_transcript_exon_variant	6/6	3
HAAO	ENST00000406007.6	n.192A>G		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 358 AN: 152230 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00252 AC: 632 AN: 251112 Hom.: 1 AF XY: 0.00256 AC XY: 347 AN XY: 135712

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.00275

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00250 AC: 3660 AN: 1461436 Hom.: 8 Cov.: 31 AF XY: 0.00239 AC XY: 1741 AN XY: 727052

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.000804

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00972

Gnomad4 NFE exome AF: 0.00262

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00234 AC: 356 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.00247 AC XY: 184 AN XY: 74500

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0108

Gnomad4 NFE AF: 0.00275

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00213 Hom.: 1

Bravo AF: 0.00164

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00254 AC: 308

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00279

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 17, 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	Benign	0.075
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	17
Dann	Benign	0.75
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.013
Sift	Benign	0.18	T
Sift4G	Benign	0.23	T
Polyphen		0.015	B
Vest4		0.19
MVP		0.15
MPC		0.072
ClinPred		0.0075	T
GERP RS		0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs113019865; hg19: chr2-42995058; COSMIC: COSV54311886; COSMIC: COSV54311886;