rs2010657

Variant names:

• chr22-24607955-G-A
• rs2010657
• NM_001288833.2:c.-427G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001288833.2(GGT1):​c.-427G>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 151,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 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: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GGT1 NM_001288833.2 splice_region
• Scores: Splicing: ADA: 0.0001817
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.551
• Publications: 2 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGT1	NM_001288833.2	c.-427G>A		splice_region_variant	Exon 2 of 16	ENST00000400382.6	NP_001275762.1
GGT1	NM_001288833.2	c.-427G>A		5_prime_UTR_variant	Exon 2 of 16	ENST00000400382.6	NP_001275762.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGT1	ENST00000400382.6	c.-427G>A		splice_region_variant	Exon 2 of 16	2	NM_001288833.2	ENSP00000383232.1
ENSG00000286070	ENST00000652248.1	n.*169G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 20			ENSP00000499210.1
GGT1	ENST00000400382.6	c.-427G>A		5_prime_UTR_variant	Exon 2 of 16	2	NM_001288833.2	ENSP00000383232.1
ENSG00000286070	ENST00000652248.1	n.*169G>A		3_prime_UTR_variant	Exon 6 of 20			ENSP00000499210.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 151794 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000436

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000977

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000368 AC: 54 AN: 146608 AF XY: 0.000380

Gnomad AFR exome AF: 0.000902

Gnomad AMR exome AF: 0.000249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00373

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000181 AC: 57 AN: 315122 Hom.: 0 Cov.: 0 AF XY: 0.000191 AC XY: 34 AN XY: 178272

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

African (AFR) AF: 0.000593 AC: 5 AN: 8430

American (AMR) AF: 0.000148 AC: 4 AN: 27106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10748

East Asian (EAS) AF: 0.00425 AC: 37 AN: 8712

South Asian (SAS) AF: 0.0000337 AC: 2 AN: 59394

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1274

European-Non Finnish (NFE) AF: 0.0000442 AC: 7 AN: 158350

Other (OTH) AF: 0.000142 AC: 2 AN: 14066

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000250 AC: 38 AN: 151912 Hom.: 0 Cov.: 32 AF XY: 0.000310 AC XY: 23 AN XY: 74250

African (AFR) AF: 0.000435 AC: 18 AN: 41390

American (AMR) AF: 0.000328 AC: 5 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000979 AC: 5 AN: 5106

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67964

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000203 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	17
DANN	Benign	0.56
PhyloP100		-0.55
PromoterAI		-0.19	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.89		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2010657; hg19: chr22-25003922;