chr10-124403003-C-T

Position:

• chr10-124403003-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000274.4(OAT):​c.824G>A​(p.Trp275*) 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: OAT NM_000274.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.75

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 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 10-124403003-C-T is Pathogenic according to our data. Variant chr10-124403003-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-124403003-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OAT	NM_000274.4	c.824G>A	p.Trp275*	stop_gained	7/10	ENST00000368845.6	NP_000265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OAT	ENST00000368845.6	c.824G>A	p.Trp275*	stop_gained	7/10	1	NM_000274.4	ENSP00000357838.5
OAT	ENST00000539214.5	c.410G>A	p.Trp137*	stop_gained	6/9	1		ENSP00000439042.1
OAT	ENST00000467675.5	n.625G>A		non_coding_transcript_exon_variant	6/7	5
OAT	ENST00000471127.1	n.334G>A		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251194 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135880

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine aminotransferase deficiency Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 31, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 06, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 29, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 21, 2023	This sequence change creates a premature translational stop signal (p.Trp275*) in the OAT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OAT are known to be pathogenic (PMID: 1737786, 23076989). This variant is present in population databases (rs267606924, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with OAT-related conditions. ClinVar contains an entry for this variant (Variation ID: 180). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.93	D
Vest4		0.97
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs267606924; hg19: chr10-126091572;