rs386833611

Variant names:

• chr10-124408575-TGCCCTTCACGGTATA-T
• rs386833611
• NM_000274.4:c.472_486delTATACCGTGAAGGGC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM4 PP3 PP5_Moderate

The NM_000274.4(OAT):​c.472_486delTATACCGTGAAGGGC​(p.Tyr158_Gly162del) variant causes a conservative inframe deletion 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 DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: OAT NM_000274.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.66
• Publications: 1 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000274.4
• PM4: Nonframeshift variant in NON repetitive region in NM_000274.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 10-124408575-TGCCCTTCACGGTATA-T is Pathogenic according to our data. Variant chr10-124408575-TGCCCTTCACGGTATA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 56129.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OAT	NM_000274.4	MANE Select	c.472_486delTATACCGTGAAGGGC	p.Tyr158_Gly162del	conservative_inframe_deletion	Exon 4 of 10	NP_000265.1
	OAT	NM_001322965.2		c.472_486delTATACCGTGAAGGGC	p.Tyr158_Gly162del	conservative_inframe_deletion	Exon 4 of 10	NP_001309894.1
	OAT	NM_001322966.2		c.472_486delTATACCGTGAAGGGC	p.Tyr158_Gly162del	conservative_inframe_deletion	Exon 5 of 11	NP_001309895.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OAT	ENST00000368845.6	TSL:1 MANE Select	c.472_486delTATACCGTGAAGGGC	p.Tyr158_Gly162del	conservative_inframe_deletion	Exon 4 of 10	ENSP00000357838.5
	OAT	ENST00000539214.5	TSL:1	c.58_72delTATACCGTGAAGGGC	p.Tyr20_Gly24del	conservative_inframe_deletion	Exon 3 of 9	ENSP00000439042.1
	OAT	ENST00000467675.5	TSL:5	n.99_113delTATACCGTGAAGGGC		non_coding_transcript_exon	Exon 2 of 7

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine aminotransferase deficiency Pathogenic:2

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.472_486del, results in the deletion of 5 amino acid(s) of the OAT protein (p.Tyr158_Gly162del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with gyrate atrophy of the choroid and retina (PMID: 1301936). ClinVar contains an entry for this variant (Variation ID: 56129). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the OAT protein in which other variant(s) (p.Tyr158Ser) have been determined to be pathogenic (PMID: 29757052). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs386833611; hg19: chr10-126097144;