rs121965044

Variant names:

• chr10-124398012-G-A
• rs121965044
• NM_000274.4:c.1250C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-124398012-G-A
• chr10-124398012-G-T

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000274.4(OAT):​c.1250C>T​(p.Pro417Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,613,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000626796: Experimental studies have shown that this missense change affects OAT function (PMID:1737786, 23076989)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P417S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: OAT NM_000274.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.48
• Publications: 9 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: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000626796: Experimental studies have shown that this missense change affects OAT function (PMID: 1737786, 23076989).; SCV000914446: The variant was expressed independently in Chinese hamster ovary (CHO) cells and yielded low levels of OAT antigen and absence of OAT activity (Brody et al. 1992). The p.Pro417Leu variant was also expressed in yeast and was found to have less than ten percent of OAT activity compared to wild type and failed to act as a functional complement to allow growth of a yeast strain containing a deletion variant of the CargB gene (Doimo et al. 2013).; SCV006323250: Relevant functional assessments of this variant are available in the literature (PMID: 23076989, 1737786).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-124398013-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1466306.
• 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: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 10-124398012-G-A is Pathogenic according to our data. Variant chr10-124398012-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OAT	NM_000274.4	MANE Select	c.1250C>T	p.Pro417Leu	missense	Exon 10 of 10	NP_000265.1	P04181-1
	OAT	NM_001322965.2		c.1250C>T	p.Pro417Leu	missense	Exon 10 of 10	NP_001309894.1	P04181-1
	OAT	NM_001322966.2		c.1250C>T	p.Pro417Leu	missense	Exon 11 of 11	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.1250C>T	p.Pro417Leu	missense	Exon 10 of 10	ENSP00000357838.5	P04181-1
	OAT	ENST00000539214.5	TSL:1	c.836C>T	p.Pro279Leu	missense	Exon 9 of 9	ENSP00000439042.1	P04181-2
	OAT	ENST00000921313.1		c.1253C>T	p.Pro418Leu	missense	Exon 10 of 10	ENSP00000591372.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152136 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250978 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000636 AC: 93 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.0000633 AC XY: 46 AN XY: 727178

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000737 AC: 82 AN: 1111910

Other (OTH) AF: 0.0000828 AC: 5 AN: 60388

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152136 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74328

African (AFR) AF: 0.0000242 AC: 1 AN: 41406

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: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Ornithine aminotransferase deficiency (9)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.0	H
PhyloP100		9.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-9.7	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.98
MPC		0.85
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.99
gMVP		0.96
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs121965044; hg19: chr10-126086581; COSMIC: COSV64347444; COSMIC: COSV64347444;