16-58709490-C-A

Variant names:

• chr16-58709490-C-A
• rs1597696047
• NM_002080.4:c.1097G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_002080.4(GOT2):​c.1097G>T​(p.Gly366Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,588 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 (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GOT2 NM_002080.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.80

Genes affected

GOT2 (HGNC:4433): (glutamic-oxaloacetic transaminase 2) Glutamic-oxaloacetic transaminase is a pyridoxal phosphate-dependent enzyme which exists in cytoplasmic and inner-membrane mitochondrial forms, GOT1 and GOT2, respectively. GOT plays a role in amino acid metabolism and the urea and tricarboxylic acid cycles. The two enzymes are homodimeric and show close homology. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2013]

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874
• PP5: Variant 16-58709490-C-A is Pathogenic according to our data. Variant chr16-58709490-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 691281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GOT2	NM_002080.4	c.1097G>T	p.Gly366Val	missense_variant	Exon 9 of 10	ENST00000245206.10	NP_002071.2
GOT2	NM_001286220.2	c.968G>T	p.Gly323Val	missense_variant	Exon 8 of 9		NP_001273149.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GOT2	ENST00000245206.10	c.1097G>T	p.Gly366Val	missense_variant	Exon 9 of 10	1	NM_002080.4	ENSP00000245206.5
GOT2	ENST00000434819.2	c.968G>T	p.Gly323Val	missense_variant	Exon 8 of 9	2		ENSP00000394100.2
GOT2	ENST00000494627.1	n.448G>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461588 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727084

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33478

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44718

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26132

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39692

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86246

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53414

Gnomad4 NFE exome AF: 8.99e-7 AC: 1 AN: 1111758

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy Pathogenic:2

Jul 17, 2019

TIDEX, University of British Columbia

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 29, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The homozygous p.Gly366Val variant in GOT2 was identified by our study in one Egyptian individual with early infantile epileptic encephalopathy (PMID: 31422819). This variant was absent from large population studies. This variant has also been reported in ClinVar as pathogenic by OMIM and likely pathogenic by TIDEX, University of British Columbia (Variation ID: 691281). In vitro functional studies provide some evidence that the variant may slightly impact protein function (PMID: 31422819). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PM3_supporting, PS3_moderate (Richards 2015). -

Developmental and epileptic encephalopathy, 82 Pathogenic:1

Oct 11, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-8.6	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.99	D;.
Vest4		0.92
MutPred		0.64		Loss of helix (P = 0.0041);.;
MVP		0.92
MPC		1.2
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.91
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

Publications

LitVar

Other links and lift over

dbSNP: rs1597696047; hg19: chr16-58743394;