NM_000274.4:c.267C>A

Variant names:

• chr10-124408898-G-T
• rs386833602
• NM_000274.4:c.267C>A
• OAT p.Asn89Lys

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000274.4(OAT):​c.267C>A​(p.Asn89Lys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N89S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: OAT NM_000274.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.19
• Publications: 6 publications found

Genes affected

OAT (HGNC:8091): (ornithine aminotransferase) This gene encodes the mitochondrial enzyme ornithine aminotransferase, which is a key enzyme in the pathway that converts arginine and ornithine into the major excitatory and inhibitory neurotransmitters glutamate and GABA. Mutations that result in a deficiency of this enzyme cause the autosomal recessive eye disease Gyrate Atrophy. Alternatively spliced transcript variants encoding different isoforms have been described. Related pseudogenes have been defined on the X chromosome. [provided by RefSeq, Jan 2010]

OAT Gene-Disease associations (from GenCC):

• ornithine aminotransferase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000274.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 35 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.87566 (below the threshold of 3.09). Trascript score misZ: 1.6556 (below the threshold of 3.09). GenCC associations: The gene is linked to ornithine aminotransferase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 10-124408898-G-T is Pathogenic according to our data. Variant chr10-124408898-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 56120.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000274.4. 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
	OAT	NM_000274.4	MANE Select	c.267C>A	p.Asn89Lys	missense	Exon 3 of 10	NP_000265.1	P04181-1
	OAT	NM_001322965.2		c.267C>A	p.Asn89Lys	missense	Exon 3 of 10	NP_001309894.1	P04181-1
	OAT	NM_001322966.2		c.267C>A	p.Asn89Lys	missense	Exon 4 of 11	NP_001309895.1	P04181-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OAT	ENST00000368845.6	TSL:1 MANE Select	c.267C>A	p.Asn89Lys	missense	Exon 3 of 10	ENSP00000357838.5	P04181-1
	OAT	ENST00000539214.5	TSL:1	c.-148C>A		5_prime_UTR	Exon 2 of 9	ENSP00000439042.1	P04181-2
	OAT	ENST00000921313.1		c.267C>A	p.Asn89Lys	missense	Exon 3 of 10	ENSP00000591372.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Ornithine aminotransferase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		3.2
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.99
gMVP		0.97
Mutation Taster		=8/92	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs386833602; hg19: chr10-126097467;