22-24603137-C-G

Variant names:

• chr22-24603137-C-G
• rs2073398
• ENST00000652248.1:n.*168-4817C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000652248.1(ENSG00000286070):​n.*168-4817C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 150,638 control chromosomes in the GnomAD database, including 8,307 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (8307 hom., cov: 31)
  • Exomes 𝑓: 0.045 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENSG00000286070 ENST00000652248.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.384
• Publications: 19 publications found

Genes affected

ENSG00000286070 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000652248.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGT1	NM_013430.3		c.-428-4817C>G		intron	N/A	NP_038347.2
	GGT1	NM_001288833.2	MANE Select	c.-819C>G		upstream_gene	N/A	NP_001275762.1
	GGT1	NM_013421.3		c.-747C>G		upstream_gene	N/A	NP_038265.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000286070	ENST00000652248.1		n.*168-4817C>G		intron	N/A	ENSP00000499210.1
	GGT1	ENST00000411974.5	TSL:3	c.-323-4817C>G		intron	N/A	ENSP00000389935.1
	GGT1	ENST00000456869.5	TSL:3	c.-431-4817C>G		intron	N/A	ENSP00000415129.1

Frequencies

GnomAD3 genomes AF: 0.325 AC: 48970 AN: 150520 Hom.: 8299 Cov.: 31

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.261

Gnomad AMR AF: 0.424

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.467

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.368

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0448 AC: 6 AN: 134 Hom.: 1 Cov.: 0 AF XY: 0.0566 AC XY: 6 AN XY: 106

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 6

South Asian (SAS) AF: 0.00 AC: 0 AN: 6

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0455 AC: 5 AN: 110

Other (OTH) AF: 0.167 AC: 1 AN: 6

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0547993), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.325 AC: 48996 AN: 150638 Hom.: 8307 Cov.: 31 AF XY: 0.322 AC XY: 23648 AN XY: 73532

African (AFR) AF: 0.232 AC: 9548 AN: 41194

American (AMR) AF: 0.424 AC: 6417 AN: 15118

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 1457 AN: 3448

East Asian (EAS) AF: 0.360 AC: 1825 AN: 5066

South Asian (SAS) AF: 0.267 AC: 1277 AN: 4782

European-Finnish (FIN) AF: 0.305 AC: 3155 AN: 10332

Middle Eastern (MID) AF: 0.475 AC: 135 AN: 284

European-Non Finnish (NFE) AF: 0.359 AC: 24186 AN: 67428

Other (OTH) AF: 0.365 AC: 761 AN: 2084

Alfa AF: 0.162 Hom.: 302

Asia WGS AF: 0.324 AC: 1121 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.0
DANN	Benign	0.36
PhyloP100		0.38
PromoterAI		0.088	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs2073398; hg19: chr22-24999104; COSMIC: COSV50644300; COSMIC: COSV50644300;