chr16-46909696-A-G

Variant names:

• chr16-46909696-A-G
• rs748267502
• NM_133443.4:c.589A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_133443.4(GPT2):​c.589A>G​(p.Ile197Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GPT2 NM_133443.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.40
• Publications: 0 publications found

Genes affected

GPT2 (HGNC:18062): (glutamic--pyruvic transaminase 2) This gene encodes a mitochondrial alanine transaminase, a pyridoxal enzyme that catalyzes the reversible transamination between alanine and 2-oxoglutarate to generate pyruvate and glutamate. Alanine transaminases play roles in gluconeogenesis and amino acid metabolism in many tissues including skeletal muscle, kidney, and liver. Activating transcription factor 4 upregulates this gene under metabolic stress conditions in hepatocyte cell lines. A loss of function mutation in this gene has been associated with developmental encephalopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

GPT2 Gene-Disease associations (from GenCC):

• glutamate pyruvate transaminase 2 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.281713).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPT2	NM_133443.4	c.589A>G	p.Ile197Val	missense_variant	Exon 6 of 12	ENST00000340124.9	NP_597700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPT2	ENST00000340124.9	c.589A>G	p.Ile197Val	missense_variant	Exon 6 of 12	1	NM_133443.4	ENSP00000345282.4
GPT2	ENST00000440783.2	c.289A>G	p.Ile97Val	missense_variant	Exon 6 of 12	2		ENSP00000413804.2
GPT2	ENST00000562132.5	c.355A>G	p.Ile119Val	missense_variant	Exon 5 of 5	4		ENSP00000457475.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250566 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutamate pyruvate transaminase 2 deficiency Uncertain:2

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 06, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Uncertain	0.97
DEOGEN2	Benign	0.40	T;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.70	N;.;.
PhyloP100		2.4
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.81	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.043	D;D;D
Sift4G	Uncertain	0.051	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.35
MutPred		0.57		Gain of ubiquitination at K196 (P = 0.1111);.;.;
MVP		0.76
MPC		0.38
ClinPred		0.19	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs748267502; hg19: chr16-46943608;