rs1554867698

Positions:

• chr10-124411966-AACGTACCT-ATTAA

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_Strong PM2 PP3 PP5_Moderate

The NM_000274.4(OAT):​c.198_199+6delinsTTAA variant causes a splice donor, splice donor 5th base, coding sequence, 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: OAT NM_000274.4 splice_donor, splice_donor_5th_base, coding_sequence, 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 Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.1719697 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• 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/exons	MANE	UniProt
OAT	NM_000274.4	c.198_199+6delinsTTAA		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	2/10	ENST00000368845.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OAT	ENST00000368845.6	c.198_199+6delinsTTAA		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	2/10	1	NM_000274.4	P1

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 15, 2016

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;