rs121965047

chr10-124401746-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000274.4(OAT):c.994G>A(p.Val332Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V332V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: OAT NM_000274.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 4.75

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]

ACMG classification

Verdict is Pathogenic. Variant got 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 10-124401746-C-T is Pathogenic according to our data. Variant chr10-124401746-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 162.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-124401746-C-T is described in Lovd as [Pathogenic]. Variant chr10-124401746-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OAT	NM_000274.4	c.994G>A	p.Val332Met	missense_variant	8/10	ENST00000368845.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OAT	ENST00000368845.6	c.994G>A	p.Val332Met	missense_variant	8/10	1	NM_000274.4	P1
OAT	ENST00000539214.5	c.580G>A	p.Val194Met	missense_variant	7/9	1
OAT	ENST00000467675.5	n.795G>A		non_coding_transcript_exon_variant	7/7	5
OAT	ENST00000471127.1	n.504G>A		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250456 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135408

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460496 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine aminotransferase deficiency Pathogenic:2

Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 31, 2022	- -

Gyrate atrophy of choroid and retina with pyridoxine-responsive ornithinemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.97	.;D
Vest4		0.88
MutPred		0.91		.;Loss of methylation at R331 (P = 0.1583);
MVP		0.92
MPC		0.65
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.90
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs121965047; hg19: chr10-126090315;