22-24611214-G-A

Position:

• chr22-24611214-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001288833.2(GGT1):​c.133G>A​(p.Ala45Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000667 in 1,573,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: GGT1 NM_001288833.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.639

Genes affected

GGT1 (HGNC:4250): (gamma-glutamyltransferase 1) The enzyme encoded by this gene is a type I gamma-glutamyltransferase that catalyzes the transfer of the glutamyl moiety of glutathione to a variety of amino acids and dipeptide acceptors. The enzyme is composed of a heavy chain and a light chain, which are derived from a single precursor protein. It is expressed in tissues involved in absorption and secretion and may contribute to the etiology of diabetes and other metabolic disorders. Multiple alternatively spliced variants have been identified. There are a number of related genes present on chromosomes 20 and 22, and putative pseudogenes for this gene on chromosomes 2, 13, and 22. [provided by RefSeq, Jan 2014]

ENSG00000286070 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GGT1. . Gene score misZ 0.85745 (greater than the threshold 3.09). Trascript score misZ 3.5416 (greater than threshold 3.09). GenCC has associacion of gene with gamma-glutamyl transpeptidase deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.04337567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GGT1	NM_001288833.2	c.133G>A	p.Ala45Thr	missense_variant	5/16	ENST00000400382.6	NP_001275762.1
GGT1	NM_013421.3	c.133G>A	p.Ala45Thr	missense_variant	6/17		NP_038265.2
GGT1	NM_013430.3	c.133G>A	p.Ala45Thr	missense_variant	5/16		NP_038347.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GGT1	ENST00000400382.6	c.133G>A	p.Ala45Thr	missense_variant	5/16	2	NM_001288833.2	ENSP00000383232.1
ENSG00000286070	ENST00000652248.1	n.*623G>A		non_coding_transcript_exon_variant	9/20			ENSP00000499210.1
ENSG00000286070	ENST00000652248.1	n.*623G>A		3_prime_UTR_variant	9/20			ENSP00000499210.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152172 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000484 AC: 9 AN: 186080 Hom.: 0 AF XY: 0.0000401 AC XY: 4 AN XY: 99788

Gnomad AFR exome AF: 0.0000973

Gnomad AMR exome AF: 0.00

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: 0.000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000655 AC: 93 AN: 1420786 Hom.: 0 Cov.: 31 AF XY: 0.0000555 AC XY: 39 AN XY: 703280

Gnomad4 AFR exome AF: 0.0000307

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000106

Gnomad4 SAS exome AF: 0.0000613

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000715

Gnomad4 OTH exome AF: 0.0000851

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152290 Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5 AN XY: 74460

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.0000669 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2023

The c.133G>A (p.A45T) alteration is located in exon 5 (coding exon 1) of the GGT1 gene. This alteration results from a G to A substitution at nucleotide position 133, causing the alanine (A) at amino acid position 45 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.91
DANN	Benign	0.86
DEOGEN2	Benign	0.13	T;.;.;.;T;T;T;.;T;.;.;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.029	N
LIST_S2	Uncertain	0.92	.;D;D;D;D;.;D;D;D;D;T;.;D;D;D
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.043	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.94	L;.;.;.;.;L;.;.;L;.;.;.;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.23	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.71	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.71	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.042	B;.;.;.;.;B;.;.;B;.;.;.;.;.;.
Vest4		0.091
MVP		0.38
ClinPred		0.0071	T
GERP RS		-1.3
Varity_R		0.17
gMVP		0.79

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: rs535860497; hg19: chr22-25007181;