2-42770143-C-CA

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_012205.3(HAAO):c.483dupT(p.Asp162fs) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,603,908 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

HAAO
NM_012205.3 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.06

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

vertebral, cardiac, renal, and limb defects syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
congenital vertebral-cardiac-renal anomalies syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HAAO links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-42770143-C-CA is Pathogenic according to our data. Variant chr2-42770143-C-CA is described in CliVar as Pathogenic. Clinvar id is 403727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-42770143-C-CA is described in CliVar as Pathogenic. Clinvar id is 403727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-42770143-C-CA is described in CliVar as Pathogenic. Clinvar id is 403727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-42770143-C-CA is described in CliVar as Pathogenic. Clinvar id is 403727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-42770143-C-CA is described in CliVar as Pathogenic. Clinvar id is 403727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-42770143-C-CA is described in CliVar as Pathogenic. Clinvar id is 403727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-42770143-C-CA is described in CliVar as Pathogenic. Clinvar id is 403727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-42770143-C-CA is described in CliVar as Pathogenic. Clinvar id is 403727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-42770143-C-CA is described in CliVar as Pathogenic. Clinvar id is 403727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-42770143-C-CA is described in CliVar as Pathogenic. Clinvar id is 403727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-42770143-C-CA is described in CliVar as Pathogenic. Clinvar id is 403727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-42770143-C-CA is described in CliVar as Pathogenic. Clinvar id is 403727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-42770143-C-CA is described in CliVar as Pathogenic. Clinvar id is 403727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAAO	NM_012205.3 link	c.483dupT	p.Asp162fs	frameshift_variant, splice_region_variant	Exon 6 of 10	ENST00000294973.11	NP_036337.2	P46952-1
HAAO	XM_011532729.4 link	c.393dupT	p.Asp132fs	frameshift_variant, splice_region_variant	Exon 5 of 9		XP_011531031.1
HAAO	XM_011532730.4 link	c.381dupT	p.Asp128fs	frameshift_variant, splice_region_variant	Exon 7 of 11		XP_011531032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAAO	ENST00000294973.11 link	c.483dupT	p.Asp162fs	frameshift_variant, splice_region_variant	Exon 6 of 10	1	NM_012205.3	ENSP00000294973.6		P46952-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000172

AC:

AN:

232362

AF XY:

0.0000159

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000388

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1451728

Hom.:

Cov.:

AF XY:

0.00000693

AC XY:

AN XY:

721396

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33226

American (AMR)

AF:

0.00

AC:

AN:

43874

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25892

East Asian (EAS)

AF:

0.00

AC:

AN:

39226

South Asian (SAS)

AF:

0.00

AC:

AN:

84666

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52808

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000145

AC:

AN:

1106314

Other (OTH)

AF:

0.00

AC:

AN:

59964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Vertebral, cardiac, renal, and limb defects syndrome 1

Pathogenic:2

Sep 21, 2017

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 16, 2018

SIB Swiss Institute of Bioinformatics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Pathogenic, for Vertebral, cardiac, renal, and limb defects syndrome 1, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PVS1-Strong => PVS1 downgraded in strength to Strong. PS3 => Well-established functional studies show a deleterious effect (PMID:28792876). -

Congenital NAD deficiency disorder

Pathogenic:1

Dec 23, 2016

Embryology Laboratory, Victor Chang Cardiac Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

This variant was discovered in a consanguineous family of Middle East origin. The patient presented multiple congenital malformations affecting vertebrae, heart and kidney among others. This variant is a protein truncating variant and extremely rare (ExAC MAF 0.00003005). The patient is homozygous, while his unaffected parents and four unaffected siblings are heterozygous for this variant. The patient showed increased plasma concentration of 3HAA and reduced plasma concentration of NAD, consistent with loss of function of the HAAO enzyme activity. Enzyme assay confirmed that the protein product of this gene variant has lost enzyme activity. Mouse embryos homozygous null for Haao presented similar phenotype as observed in the patient, and also showed reduced concentration of NAD in the embryonic tissue. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over