rs1554867698

Variant names:

• chr10-124411967-ACGTACCT-TTAA
• rs1554867698
• NM_000274.4:c.198_199+6delAGGTACGTinsTTAA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000274.4(OAT):​c.198_199+6delAGGTACGTinsTTAA​(p.Gly67fs) variant causes a frameshift, splice donor, splice region, synonymous, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 frameshift, splice_donor, splice_region, synonymous, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.55

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 12 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 10-124411967-ACGTACCT-TTAA is Pathogenic according to our data. Variant chr10-124411967-ACGTACCT-TTAA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 456520.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OAT	NM_000274.4	c.198_199+6delAGGTACGTinsTTAA	p.Gly67fs	frameshift_variant, splice_donor_variant, splice_region_variant, synonymous_variant, intron_variant	Exon 2 of 10	ENST00000368845.6	NP_000265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OAT	ENST00000368845.6	c.198_199+6delAGGTACGTinsTTAA	p.Gly67fs	frameshift_variant, splice_donor_variant, splice_region_variant, synonymous_variant, intron_variant	Exon 2 of 10	1	NM_000274.4	ENSP00000357838.5

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine aminotransferase deficiency Pathogenic:1

Sep 15, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes 9 nucleotides and inserts 5 nucleotides in exon 2 of the OAT mRNA (c.198_199+7delinsTTAAT). It affects the donor splice site in intron 2 of the OAT gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and loss-of-function variants in OAT are known to be pathogenic (PMID: 23076989). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic. This variant has not been reported in the literature in individuals with a OAT-related disease. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554867698; hg19: chr10-126100536;