rs4049844

Variant names:

• chr22-24620329-G-A
• rs4049844
• NM_001288833.2:c.384G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001288833.2(GGT1):​c.384G>A​(p.Gly128Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GGT1 NM_001288833.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.00001150
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.798
• Publications: 7 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP7: Synonymous conserved (PhyloP=-0.798 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGT1	NM_001288833.2	c.384G>A	p.Gly128Gly	splice_region_variant, synonymous_variant	Exon 8 of 16	ENST00000400382.6	NP_001275762.1
GGT1	NM_013421.3	c.384G>A	p.Gly128Gly	splice_region_variant, synonymous_variant	Exon 9 of 17		NP_038265.2
GGT1	NM_013430.3	c.384G>A	p.Gly128Gly	splice_region_variant, synonymous_variant	Exon 8 of 16		NP_038347.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGT1	ENST00000400382.6	c.384G>A	p.Gly128Gly	splice_region_variant, synonymous_variant	Exon 8 of 16	2	NM_001288833.2	ENSP00000383232.1
ENSG00000286070	ENST00000652248.1	n.*874G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 12 of 20			ENSP00000499210.1
ENSG00000286070	ENST00000652248.1	n.*874G>A		3_prime_UTR_variant	Exon 12 of 20			ENSP00000499210.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00219 AC: 465 AN: 211860 AF XY: 0.00149

Gnomad AFR exome AF: 0.00309

Gnomad AMR exome AF: 0.000383

Gnomad ASJ exome AF: 0.00118

Gnomad EAS exome AF: 0.000592

Gnomad FIN exome AF: 0.00312

Gnomad NFE exome AF: 0.00333

Gnomad OTH exome AF: 0.00270

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459410 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726028

⚠️ 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: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111742

Other (OTH) AF: 0.00 AC: 0 AN: 60186

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.002506), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.0338 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.20
DANN	Benign	0.85
PhyloP100		-0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.060		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: rs4049844; hg19: chr22-25016296; COSMIC: COSV50639933; COSMIC: COSV50639933;