rs1437184398

Variant names:

• chr16-46884785-C-T
• rs1437184398
• NM_133443.4:c.70C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_133443.4(GPT2):​c.70C>T​(p.Gln24*) 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 NM_133443.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 1.11
• 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: Pathogenic. The variant received 12 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 20 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 VariationId is 522105.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPT2	NM_133443.4	c.70C>T	p.Gln24*	stop_gained	Exon 2 of 12	ENST00000340124.9	NP_597700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPT2	ENST00000340124.9	c.70C>T	p.Gln24*	stop_gained	Exon 2 of 12	1	NM_133443.4	ENSP00000345282.4
GPT2	ENST00000562132.5	c.9+61C>T		intron_variant	Intron 1 of 4	4		ENSP00000457475.1
GPT2	ENST00000440783.2	c.-715C>T		upstream_gene_variant		2		ENSP00000413804.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000725 AC: 1 AN: 138018 AF XY: 0.0000129

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 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

African (AFR) AF: 0.00 AC: 0 AN: 28092

American (AMR) AF: 0.0000324 AC: 1 AN: 30892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23146

East Asian (EAS) AF: 0.00 AC: 0 AN: 32092

South Asian (SAS) AF: 0.00 AC: 0 AN: 75580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5062

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1064626

Other (OTH) AF: 0.00 AC: 0 AN: 55990

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

Aug 01, 2019

Section for Clinical Neurogenetics, University of Tübingen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 05, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Nov 03, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		1.1
Vest4		0.44
GERP RS		1.8
PromoterAI		-0.066	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=3/197	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

Other links and lift over

dbSNP: rs1437184398; hg19: chr16-46918697;