Genetic Variant OAT:p.Met1? (chr10-124412169-C-T) – ACMG Classification: Pathogenic (20 pts)

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_000274.4(OAT):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,262 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

OAT
NM_000274.4 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.29

Publications

3 publications found

Variant links:

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)

OAT links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 26 pathogenic variants. Next in-frame start position is after 139 codons. Genomic position: 124408750. Lost 0.314 part of the original CDS.

PS1

Another start lost variant in NM_000274.4 (OAT) was described as [Pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-124412169-C-T is Pathogenic according to our data. Variant chr10-124412169-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 146.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OAT	NM_000274.4	MANE Select	c.3G>A	p.Met1?	start_lost	Exon 2 of 10	NP_000265.1	P04181-1
OAT	NM_001322965.2		c.3G>A	p.Met1?	start_lost	Exon 2 of 10	NP_001309894.1	P04181-1
OAT	NM_001322966.2		c.3G>A	p.Met1?	start_lost	Exon 3 of 11	NP_001309895.1	P04181-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OAT	ENST00000368845.6	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 2 of 10	ENSP00000357838.5	P04181-1
OAT	ENST00000539214.5	TSL:1	c.-215-3204G>A		intron	N/A	ENSP00000439042.1	P04181-2
OAT	ENST00000921313.1		c.3G>A	p.Met1?	start_lost	Exon 2 of 10	ENSP00000591372.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461262

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726952

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53152

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5634

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111838

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ornithine aminotransferase deficiency (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.42

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.87

PhyloP100

6.3

PROVEAN

Benign

-0.72

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.041

Polyphen

0.94

Vest4

0.96

MutPred

0.99

Gain of helix (P = 0.0425)

MVP

0.96

ClinPred

0.99

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.74

Mutation Taster

=10/190

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over