rs1063739

Positions:

• chr8-144504344-C-A
• chr8-144504344-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005309.3(GPT):​c.40C>A​(p.His14Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 1,610,178 control chromosomes in the GnomAD database, including 178,460 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.42 (14304 hom., cov: 35)
  • Exomes 𝑓: 0.47 (164156 hom.)
• Consequence: GPT NM_005309.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72

Genes affected

GPT (HGNC:4552): (glutamic--pyruvic transaminase) This gene encodes cytosolic alanine aminotransaminase 1 (ALT1); also known as glutamate-pyruvate transaminase 1. This enzyme catalyzes the reversible transamination between alanine and 2-oxoglutarate to generate pyruvate and glutamate and, therefore, plays a key role in the intermediary metabolism of glucose and amino acids. Serum activity levels of this enzyme are routinely used as a biomarker of liver injury caused by drug toxicity, infection, alcohol, and steatosis. A related gene on chromosome 16 encodes a putative mitochondrial alanine aminotransaminase.[provided by RefSeq, Nov 2009]

ENSG00000255182 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.262394E-5).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPT	NM_005309.3	c.40C>A	p.His14Asn	missense_variant	1/11	ENST00000394955.3	NP_005300.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPT	ENST00000394955.3	c.40C>A	p.His14Asn	missense_variant	1/11	1	NM_005309.3	ENSP00000378408.2

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63355 AN: 152052 Hom.: 14299 Cov.: 35

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.520

Gnomad ASJ AF: 0.429

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.576

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.446

GnomAD3 exomes AF: 0.482 AC: 119112 AN: 247036 Hom.: 29518 AF XY: 0.487 AC XY: 65323 AN XY: 134238

Gnomad AFR exome AF: 0.226

Gnomad AMR exome AF: 0.567

Gnomad ASJ exome AF: 0.456

Gnomad EAS exome AF: 0.494

Gnomad SAS exome AF: 0.557

Gnomad FIN exome AF: 0.493

Gnomad NFE exome AF: 0.472

Gnomad OTH exome AF: 0.470

GnomAD4 exome AF: 0.471 AC: 687172 AN: 1458008 Hom.: 164156 Cov.: 56 AF XY: 0.475 AC XY: 344635 AN XY: 725480

Gnomad4 AFR exome AF: 0.224

Gnomad4 AMR exome AF: 0.556

Gnomad4 ASJ exome AF: 0.446

Gnomad4 EAS exome AF: 0.444

Gnomad4 SAS exome AF: 0.556

Gnomad4 FIN exome AF: 0.495

Gnomad4 NFE exome AF: 0.470

Gnomad4 OTH exome AF: 0.459

GnomAD4 genome AF: 0.417 AC: 63383 AN: 152170 Hom.: 14304 Cov.: 35 AF XY: 0.423 AC XY: 31450 AN XY: 74402

Gnomad4 AFR AF: 0.236

Gnomad4 AMR AF: 0.521

Gnomad4 ASJ AF: 0.429

Gnomad4 EAS AF: 0.490

Gnomad4 SAS AF: 0.576

Gnomad4 FIN AF: 0.500

Gnomad4 NFE AF: 0.474

Gnomad4 OTH AF: 0.443

Alfa AF: 0.466 Hom.: 31416

Bravo AF: 0.410

TwinsUK AF: 0.460 AC: 1704

ALSPAC AF: 0.471 AC: 1814

ESP6500AA AF: 0.232 AC: 1020

ESP6500EA AF: 0.465 AC: 4001

ExAC AF: 0.472 AC: 57114

Asia WGS AF: 0.538 AC: 1870 AN: 3478

EpiCase AF: 0.472

EpiControl AF: 0.474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.8
DANN	Benign	0.55
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.14	.;T
MetaRNN	Benign	0.000063	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.9	N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	1.6	N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.15
MPC		0.068
ClinPred		0.0029	T
GERP RS		3.9
Varity_R		0.037
gMVP		0.51

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: rs1063739; hg19: chr8-145729727; COSMIC: COSV52952357; COSMIC: COSV52952357;