22-24614614-CAAAAAAAAAAAA-CAAAAAAAAA

Variant names:

• chr22-24614614-CAAA-C
• rs4049879
• NM_001288833.2:c.165-147_165-145delAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001288833.2(GGT1):​c.165-147_165-145delAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 68,598 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.00013 (0 hom., cov: 29)
• Consequence: GGT1 NM_001288833.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.27
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.165-147_165-145delAAA		intron	N/A	NP_001275762.1	P19440-1
	GGT1	NM_013421.3		c.165-147_165-145delAAA		intron	N/A	NP_038265.2	A0A140VJJ9
	GGT1	NM_013430.3		c.165-147_165-145delAAA		intron	N/A	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.165-161_165-159delAAA		intron	N/A	ENSP00000383232.1	P19440-1
	GGT1	ENST00000400380.5	TSL:1	c.165-161_165-159delAAA		intron	N/A	ENSP00000383231.1	P19440-1
	ENSG00000286070	ENST00000652248.1		n.*655-161_*655-159delAAA		intron	N/A	ENSP00000499210.1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 9 AN: 68598 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000343

Gnomad ASJ AF: 0.000583

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000343

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.000131 AC: 9 AN: 68598 Hom.: 0 Cov.: 29 AF XY: 0.000155 AC XY: 5 AN XY: 32156

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

African (AFR) AF: 0.000207 AC: 5 AN: 24182

American (AMR) AF: 0.000343 AC: 2 AN: 5832

Ashkenazi Jewish (ASJ) AF: 0.000583 AC: 1 AN: 1716

East Asian (EAS) AF: 0.00 AC: 0 AN: 2062

South Asian (SAS) AF: 0.00 AC: 0 AN: 1870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 82

European-Non Finnish (NFE) AF: 0.0000343 AC: 1 AN: 29162

Other (OTH) AF: 0.00 AC: 0 AN: 904

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0170080), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3

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: rs4049879; hg19: chr22-25010581;