chr22-24611235-A-G

Position:

• chr22-24611235-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_001288833.2(GGT1):​c.154A>G​(p.Lys52Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00356 in 1,533,526 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0061 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0033 (17 hom.)
• Consequence: GGT1 NM_001288833.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.25

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 Benign. Variant got -9 ACMG points.

• 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=0.004201293).
• BP6: Variant 22-24611235-A-G is Benign according to our data. Variant chr22-24611235-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2672900.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GGT1	NM_001288833.2	c.154A>G	p.Lys52Glu	missense_variant	5/16	ENST00000400382.6	NP_001275762.1
GGT1	NM_013421.3	c.154A>G	p.Lys52Glu	missense_variant	6/17		NP_038265.2
GGT1	NM_013430.3	c.154A>G	p.Lys52Glu	missense_variant	5/16		NP_038347.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GGT1	ENST00000400382.6	c.154A>G	p.Lys52Glu	missense_variant	5/16	2	NM_001288833.2	ENSP00000383232.1
ENSG00000286070	ENST00000652248.1	n.*644A>G		non_coding_transcript_exon_variant	9/20			ENSP00000499210.1
ENSG00000286070	ENST00000652248.1	n.*644A>G		3_prime_UTR_variant	9/20			ENSP00000499210.1

Frequencies

GnomAD3 genomes AF: 0.00610 AC: 916 AN: 150218 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00184

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00926

Gnomad OTH AF: 0.00435

GnomAD3 exomes AF: 0.00243 AC: 401 AN: 165254 Hom.: 6 AF XY: 0.00215 AC XY: 190 AN XY: 88454

Gnomad AFR exome AF: 0.000548

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000245

Gnomad SAS exome AF: 0.000593

Gnomad FIN exome AF: 0.00805

Gnomad NFE exome AF: 0.00268

Gnomad OTH exome AF: 0.000867

GnomAD4 exome AF: 0.00328 AC: 4535 AN: 1383196 Hom.: 17 Cov.: 30 AF XY: 0.00324 AC XY: 2220 AN XY: 684370

Gnomad4 AFR exome AF: 0.000719

Gnomad4 AMR exome AF: 0.00669

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000273

Gnomad4 SAS exome AF: 0.000939

Gnomad4 FIN exome AF: 0.0113

Gnomad4 NFE exome AF: 0.00324

Gnomad4 OTH exome AF: 0.00343

GnomAD4 genome AF: 0.00611 AC: 919 AN: 150330 Hom.: 2 Cov.: 31 AF XY: 0.00589 AC XY: 432 AN XY: 73404

Gnomad4 AFR AF: 0.00186

Gnomad4 AMR AF: 0.00571

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00167

Gnomad4 FIN AF: 0.0106

Gnomad4 NFE AF: 0.00926

Gnomad4 OTH AF: 0.00431

Alfa AF: 0.00322 Hom.: 2

ExAC AF: 0.00102 AC: 119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

GGT1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.83
DEOGEN2	Benign	0.11	T;.;.;.;T;T;T;.;T;.;.;.;.;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.61	.;T;T;T;T;.;T;T;T;T;T;.;T;T;T
MetaRNN	Benign	0.0042	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.4	N;.;.;.;.;N;.;.;N;.;.;.;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	1.9	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.053
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;B;.;.;B;.;.;.;.;.;.
Vest4		0.083
MVP		0.11
ClinPred		0.0028	T
GERP RS		3.5
Varity_R		0.35
gMVP		0.61

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: rs2330838; hg19: chr22-25007202; COSMIC: COSV50638187; COSMIC: COSV50638187;