rs146882296

Variant names:

• chr10-124403833-G-A
• rs146882296
• NM_000274.4:c.736C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000274.4(OAT):​c.736C>T​(p.Leu246Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.000278 in 1,614,136 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).

• Frequency:
  • Genomes: 𝑓 0.00018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: OAT NM_000274.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 4.70
• Publications: 0 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 10-124403833-G-A is Benign according to our data. Variant chr10-124403833-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 526626.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000288 (421/1461844) while in subpopulation EAS AF = 0.0039 (155/39700). AF 95% confidence interval is 0.0034. There are 1 homozygotes in GnomAdExome4. There are 213 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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.736C>T	p.Leu246Leu	synonymous	Exon 6 of 10	NP_000265.1	P04181-1
	OAT	NM_001322965.2		c.736C>T	p.Leu246Leu	synonymous	Exon 6 of 10	NP_001309894.1	P04181-1
	OAT	NM_001322966.2		c.736C>T	p.Leu246Leu	synonymous	Exon 7 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.736C>T	p.Leu246Leu	synonymous	Exon 6 of 10	ENSP00000357838.5	P04181-1
	OAT	ENST00000539214.5	TSL:1	c.322C>T	p.Leu108Leu	synonymous	Exon 5 of 9	ENSP00000439042.1	P04181-2
	OAT	ENST00000921313.1		c.736C>T	p.Leu246Leu	synonymous	Exon 6 of 10	ENSP00000591372.1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000346 AC: 87 AN: 251468 AF XY: 0.000361

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00147

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000288 AC: 421 AN: 1461844 Hom.: 1 Cov.: 32 AF XY: 0.000293 AC XY: 213 AN XY: 727232

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 39 AN: 26134

East Asian (EAS) AF: 0.00390 AC: 155 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86256

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000173 AC: 192 AN: 1111982

Other (OTH) AF: 0.000331 AC: 20 AN: 60392

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74456

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000294 Hom.: 0

Bravo AF: 0.000162

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Ornithine aminotransferase deficiency (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.0
DANN	Benign	0.82
PhyloP100		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs146882296; hg19: chr10-126092402;