7-30497160-C-T

Variant names:

• chr7-30497160-C-T
• rs1301812434
• NM_024051.4:c.499G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024051.4(GGCT):​c.499G>A​(p.Asp167Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,609,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GGCT NM_024051.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.540
• Publications: 16 publications found

Genes affected

GGCT (HGNC:21705): (gamma-glutamylcyclotransferase) The protein encoded by this gene catalyzes the formation of 5-oxoproline from gamma-glutamyl dipeptides, the penultimate step in glutathione catabolism, and may play a critical role in glutathione homeostasis. The encoded protein may also play a role in cell proliferation, and the expression of this gene is a potential marker for cancer. Pseudogenes of this gene are located on the long arm of chromosome 5 and the short arm of chromosomes 2 and 20. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

ENSG00000281039 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.086501926).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024051.4. 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
	GGCT	NM_024051.4	MANE Select	c.499G>A	p.Asp167Asn	missense	Exon 4 of 4	NP_076956.1	O75223-1
	GGCT	NM_001199817.2		c.217G>A	p.Asp73Asn	missense	Exon 2 of 2	NP_001186746.1	O75223-3
	GGCT	NM_001199815.2		c.*18G>A		3_prime_UTR	Exon 4 of 4	NP_001186744.1	O75223-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGCT	ENST00000275428.9	TSL:1 MANE Select	c.499G>A	p.Asp167Asn	missense	Exon 4 of 4	ENSP00000275428.4	O75223-1
	ENSG00000281039	ENST00000598361.4	TSL:5	c.244G>A	p.Asp82Asn	missense	Exon 5 of 5	ENSP00000470615.1	M0QZK8
	GGCT	ENST00000005374.10	TSL:1	c.*18G>A		3_prime_UTR	Exon 3 of 3	ENSP00000005374.6	O75223-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249674 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457128 Hom.: 0 Cov.: 27 AF XY: 0.00000276 AC XY: 2 AN XY: 725264

African (AFR) AF: 0.00 AC: 0 AN: 33348

American (AMR) AF: 0.00 AC: 0 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108142

Other (OTH) AF: 0.0000166 AC: 1 AN: 60198

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

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

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.58
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.58	N
PhyloP100		0.54
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.028
Sift	Benign	0.97	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.064
MutPred		0.33		Gain of catalytic residue at D167 (P = 0.0438)
MVP		0.31
MPC		0.33
ClinPred		0.071	T
GERP RS		1.4
Varity_R		0.091
gMVP		0.29
Mutation Taster		=82/18	polymorphism

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: rs1301812434; hg19: chr7-30536776;