rs751587531

Variant names:

• chr22-24611208-G-A
• rs751587531
• NM_001288833.2:c.127G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001288833.2(GGT1):​c.127G>A​(p.Val43Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,424,878 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GGT1 NM_001288833.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.98
• Publications: 15 publications found

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]

GGT1 Gene-Disease associations (from GenCC):

• gamma-glutamyl transpeptidase deficiency

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics

ENSG00000286070 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001288833.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGT1	NM_001288833.2	MANE Select	c.127G>A	p.Val43Met	missense	Exon 5 of 16	NP_001275762.1	P19440-1
	GGT1	NM_013421.3		c.127G>A	p.Val43Met	missense	Exon 6 of 17	NP_038265.2	A0A140VJJ9
	GGT1	NM_013430.3		c.127G>A	p.Val43Met	missense	Exon 5 of 16	NP_038347.2	P19440-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGT1	ENST00000400382.6	TSL:2 MANE Select	c.127G>A	p.Val43Met	missense	Exon 5 of 16	ENSP00000383232.1	P19440-1
	GGT1	ENST00000400380.5	TSL:1	c.127G>A	p.Val43Met	missense	Exon 6 of 17	ENSP00000383231.1	P19440-1
	ENSG00000286070	ENST00000652248.1		n.*617G>A		non_coding_transcript_exon	Exon 9 of 20	ENSP00000499210.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152124 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000312 AC: 6 AN: 192334 AF XY: 0.0000387

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000708

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000211 AC: 30 AN: 1424878 Hom.: 0 Cov.: 31 AF XY: 0.0000198 AC XY: 14 AN XY: 705644

African (AFR) AF: 0.00 AC: 0 AN: 32696

American (AMR) AF: 0.00 AC: 0 AN: 39392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25482

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38110

South Asian (SAS) AF: 0.0000978 AC: 8 AN: 81808

European-Finnish (FIN) AF: 0.0000589 AC: 3 AN: 50950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4084

European-Non Finnish (NFE) AF: 0.0000146 AC: 16 AN: 1093450

Other (OTH) AF: 0.0000340 AC: 2 AN: 58906

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 152124 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74304

African (AFR) AF: 0.00 AC: 0 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000334 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	gamma-Glutamyltransferase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.91
MutPred		0.81		Loss of sheet (P = 0.0817)
MVP		0.64
ClinPred		0.79	D
GERP RS		3.5
Varity_R		0.48
gMVP		0.93
Mutation Taster		=42/58	disease causing

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: rs751587531; hg19: chr22-25007175; COSMIC: COSV108750331; COSMIC: COSV108750331;