chr10-124397951-C-A

Variant names:

• chr10-124397951-C-A
• rs1800456
• NM_000274.4:c.1311G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_000274.4(OAT):​c.1311G>T​(p.Leu437Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000776 in 1,613,670 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L437L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (2 hom.)
• Consequence: OAT NM_000274.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:4
• Conservation: PhyloP100: 4.64
• Publications: 5 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_benign. The variant received -6 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21116528).
• BP6: Variant 10-124397951-C-A is Benign according to our data. Variant chr10-124397951-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 56116.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.1311G>T	p.Leu437Phe	missense	Exon 10 of 10	NP_000265.1
	OAT	NM_001322965.2		c.1311G>T	p.Leu437Phe	missense	Exon 10 of 10	NP_001309894.1
	OAT	NM_001322966.2		c.1311G>T	p.Leu437Phe	missense	Exon 11 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.1311G>T	p.Leu437Phe	missense	Exon 10 of 10	ENSP00000357838.5
	OAT	ENST00000539214.5	TSL:1	c.897G>T	p.Leu299Phe	missense	Exon 9 of 9	ENSP00000439042.1
	OAT	ENST00000471127.1	TSL:2	n.*70G>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000280 AC: 70 AN: 249800 AF XY: 0.000288

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000560

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000821 AC: 1200 AN: 1461490 Hom.: 2 Cov.: 31 AF XY: 0.000802 AC XY: 583 AN XY: 727036

African (AFR) AF: 0.000120 AC: 4 AN: 33472

American (AMR) AF: 0.000179 AC: 8 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00102 AC: 1135 AN: 1111822

Other (OTH) AF: 0.000861 AC: 52 AN: 60374

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74332

African (AFR) AF: 0.000241 AC: 10 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000617 AC: 42 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000185 Hom.: 0

Bravo AF: 0.000314

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000346 AC: 42

EpiCase AF: 0.000600

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ornithine aminotransferase deficiency Pathogenic:1 Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Jan 23, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Mar 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Nov 25, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: OAT c.1311G>T (p.Leu437Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 249800 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in OAT causing Ornithine Aminotransferase Deficiency (0.00028 vs 0.0011), allowing no conclusion about variant significance. However, the severity and onset age for OAT-related conditions are not compatible with observing homozygous controls in gnomAD. c.1311G>T has been reported in cis with a pathogenic variant on 1 allele (2nd allele carried pathogenic variant in trans) in the literature in at least 1 individual affected with Ornithine Aminotransferase Deficiency (example, Brody_1992, Doimo_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Ornithine Aminotransferase Deficiency. Co-occurrences with other pathogenic variant(s) have been reported (OAT c.1250C>T, p.Pro417Leu), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in patient cells, CHO cells, or yeast expression systems (example, Brody_1992, Doimo_2013). The following publications have been ascertained in the context of this evaluation (PMID: 1737786, 23076989). ClinVar contains an entry for this variant (Variation ID: 56116). Based on the evidence outlined above, the variant was classified as likely benign.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.21	T
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	1.8	L
PhyloP100		4.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.3	N
REVEL	Pathogenic	0.65
Sift	Benign	0.049	D
Sift4G	Uncertain	0.058	T
Polyphen		0.31	B
Vest4		0.31
MutPred		0.71		Gain of methylation at K434 (P = 0.0811)
MVP		0.97
MPC		0.28
ClinPred		0.042	T
GERP RS		5.1
Varity_R		0.38
gMVP		0.62
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1800456; hg19: chr10-126086520;