rs1437184398

Positions:

• chr16-46884785-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The ENST00000340124.9(GPT2):​c.70C>T​(p.Gln24Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000022 in 1,363,704 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: 0.0000022 (0 hom.)
• Consequence: GPT2 ENST00000340124.9 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 1.11

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-46884785-C-T is Pathogenic according to our data. Variant chr16-46884785-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 522105.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPT2	NM_133443.4	c.70C>T	p.Gln24Ter	stop_gained	2/12	ENST00000340124.9	NP_597700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPT2	ENST00000340124.9	c.70C>T	p.Gln24Ter	stop_gained	2/12	1	NM_133443.4	ENSP00000345282	P1
GPT2	ENST00000562132.5	c.9+61C>T		intron_variant		4		ENSP00000457475
GPT2	ENST00000440783.2			upstream_gene_variant		2		ENSP00000413804

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000725 AC: 1 AN: 138018 Hom.: 0 AF XY: 0.0000129 AC XY: 1 AN XY: 77752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000509

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000220 AC: 3 AN: 1363704 Hom.: 0 Cov.: 30 AF XY: 0.00000297 AC XY: 2 AN XY: 673304

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000324

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000188

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Glutamate pyruvate transaminase 2 deficiency Pathogenic:2

Pathogenic, no assertion criteria provided	research	Section for Clinical Neurogenetics, University of Tübingen	Aug 01, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 05, 2020	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Benign	0.14
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.13	N
MutationTaster	Benign	1.0	A
Vest4		0.44
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1437184398; hg19: chr16-46918697;