rs1135401743

Variant names:

• chr2-42769785-C-T
• rs1135401743
• NM_012205.3:c.558G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-42769785-C-T
• chr2-42769785-C-A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_012205.3(HAAO):​c.558G>A​(p.Trp186*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000540920: 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." and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HAAO NM_012205.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.03
• Publications: 2 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
• congenital vertebral-cardiac-renal anomalies syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000540920: 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.; SCV000787463: "Well-established functional studies show a deleterious effect". PMID:28792876
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-42769785-C-T is Pathogenic according to our data. Variant chr2-42769785-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 403728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012205.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAAO	NM_012205.3	MANE Select	c.558G>A	p.Trp186*	stop_gained	Exon 7 of 10	NP_036337.2	P46952-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAAO	ENST00000294973.11	TSL:1 MANE Select	c.558G>A	p.Trp186*	stop_gained	Exon 7 of 10	ENSP00000294973.6	P46952-1
	HAAO	ENST00000878444.1		c.558G>A	p.Trp186*	stop_gained	Exon 7 of 10	ENSP00000548503.1
	HAAO	ENST00000878445.1		c.633G>A	p.Trp211*	stop_gained	Exon 8 of 11	ENSP00000548504.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Vertebral, cardiac, renal, and limb defects syndrome 1 (2)
1	-	-	Congenital NAD deficiency disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Benign	0.66	D
PhyloP100		4.0
Vest4		0.36
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1135401743; hg19: chr2-42996925;