2-42767918-T-C

Position:

chr2-42767918-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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 (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 8 hom. )

Consequence

HAAO
NM_012205.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.755

Variant links:

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 links:

HAAO (HGNC:):

HAAO links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 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 no_assertion_criteria_provided, 0 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.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAAO	NM_012205.3 linkuse as main transcript	c.641A>G	p.Tyr214Cys	missense_variant	8/10	ENST00000294973.11	NP_036337.2	P46952-1
HAAO	XM_011532729.4 linkuse as main transcript	c.551A>G	p.Tyr184Cys	missense_variant	7/9		XP_011531031.1
HAAO	XM_011532730.4 linkuse as main transcript	c.539A>G	p.Tyr180Cys	missense_variant	9/11		XP_011531032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HAAO	ENST00000294973.11 linkuse as main transcript	c.641A>G	p.Tyr214Cys	missense_variant	8/10	1	NM_012205.3	ENSP00000294973.6	P46952-1
HAAO	ENST00000402698.6 linkuse as main transcript	n.985A>G		non_coding_transcript_exon_variant	7/9	5
HAAO	ENST00000404451.7 linkuse as main transcript	n.400A>G		non_coding_transcript_exon_variant	6/6	3
HAAO	ENST00000406007.6 linkuse as main transcript	n.192A>G		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes

AF:

0.00235

AC:

358

AN:

152230

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00256

AC XY:

347

AN XY:

135712

show subpopulations

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.:

Cov.:

AF XY:

0.00239

AC XY:

1741

AN XY:

727052

show subpopulations

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.:

Cov.:

AF XY:

0.00247

AC XY:

184

AN XY:

74500

show subpopulations

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.:

Bravo

AF:

0.00164

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00254

AC:

308

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00169

EpiControl

AF:

0.00279

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HAAO-related disorder

Benign:1

Benign, no assertion criteria provided

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

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.13

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.074

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0084

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.013

Sift

Benign

0.18

Sift4G

Benign

0.23

Polyphen

0.015

Vest4

0.19

MVP

0.15

MPC

0.072

ClinPred

0.0075

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over