10-124398080-ACA-CCT

Variant names:

• chr10-124398080-ACA-CCT
• NM_000274.4:c.1180_1182delTGTinsAGG
• OAT p.Cys394Arg

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM5 PP2 PP3

The NM_000274.4(OAT):​c.1180_1182delTGTinsAGG​(p.Cys394Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C394Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: OAT NM_000274.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.75
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-124398081-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 56114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1180_1182delTGTinsAGG	p.Cys394Arg	missense	N/A	NP_000265.1	P04181-1
	OAT	NM_001322965.2		c.1180_1182delTGTinsAGG	p.Cys394Arg	missense	N/A	NP_001309894.1	P04181-1
	OAT	NM_001322966.2		c.1180_1182delTGTinsAGG	p.Cys394Arg	missense	N/A	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.1180_1182delTGTinsAGG	p.Cys394Arg	missense	N/A	ENSP00000357838.5	P04181-1
	OAT	ENST00000539214.5	TSL:1	c.766_768delTGTinsAGG	p.Cys256Arg	missense	N/A	ENSP00000439042.1	P04181-2
	OAT	ENST00000921313.1		c.1183_1185delTGTinsAGG	p.Cys395Arg	missense	N/A	ENSP00000591372.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.8

Splicing

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

hg19: chr10-126086649;