22-24615070-G-T

Position:

• chr22-24615070-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001288833.2(GGT1):​c.325G>T​(p.Val109Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GGT1 NM_001288833.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

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 Uncertain_significance. Variant got 2 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=0.37358516).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GGT1	NM_001288833.2	c.325G>T	p.Val109Leu	missense_variant	7/16	ENST00000400382.6	NP_001275762.1
GGT1	NM_013421.3	c.325G>T	p.Val109Leu	missense_variant	8/17		NP_038265.2
GGT1	NM_013430.3	c.325G>T	p.Val109Leu	missense_variant	7/16		NP_038347.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GGT1	ENST00000400382.6	c.325G>T	p.Val109Leu	missense_variant	7/16	2	NM_001288833.2	ENSP00000383232.1
ENSG00000286070	ENST00000652248.1	n.*815G>T		non_coding_transcript_exon_variant	11/20			ENSP00000499210.1
ENSG00000286070	ENST00000652248.1	n.*815G>T		3_prime_UTR_variant	11/20			ENSP00000499210.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459846 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Feb 14, 2023

The c.325G>T (p.V109L) alteration is located in exon 7 (coding exon 3) of the GGT1 gene. This alteration results from a G to T substitution at nucleotide position 325, causing the valine (V) at amino acid position 109 to be replaced by a leucine (L). 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	0.33
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.;.;T;T;T;T;.;.;.;.
Eigen	Benign	-0.043
Eigen_PC	Benign	0.024
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	.;D;D;D;.;D;D;.;D;D;D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.;.;.;M;.;M;.;.;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.087
Sift	Benign	0.089	T;T;T;D;T;T;T;T;T;D;T
Sift4G	Benign	0.099	T;D;T;D;T;D;T;D;D;D;D
Polyphen		0.17	B;.;.;.;B;.;B;.;.;.;.
Vest4		0.41
MutPred		0.64		Gain of catalytic residue at V109 (P = 0.0232);Gain of catalytic residue at V109 (P = 0.0232);Gain of catalytic residue at V109 (P = 0.0232);Gain of catalytic residue at V109 (P = 0.0232);Gain of catalytic residue at V109 (P = 0.0232);Gain of catalytic residue at V109 (P = 0.0232);Gain of catalytic residue at V109 (P = 0.0232);Gain of catalytic residue at V109 (P = 0.0232);Gain of catalytic residue at V109 (P = 0.0232);Gain of catalytic residue at V109 (P = 0.0232);Gain of catalytic residue at V109 (P = 0.0232);
MVP		0.26
ClinPred		0.65	D
GERP RS		3.6
Varity_R		0.56
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-25011037;