chr7-30497171-A-T

Variant names:

• chr7-30497171-A-T
• rs913404919
• NM_024051.4:c.488T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024051.4(GGCT):​c.488T>A​(p.Ile163Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000869 in 1,610,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GGCT NM_024051.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.54
• Publications: 6 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

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.488T>A	p.Ile163Lys	missense	Exon 4 of 4	NP_076956.1	O75223-1
	GGCT	NM_001199817.2		c.206T>A	p.Ile69Lys	missense	Exon 2 of 2	NP_001186746.1	O75223-3
	GGCT	NM_001199815.2		c.*7T>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.488T>A	p.Ile163Lys	missense	Exon 4 of 4	ENSP00000275428.4	O75223-1
	ENSG00000281039	ENST00000598361.4	TSL:5	c.233T>A	p.Ile78Lys	missense	Exon 5 of 5	ENSP00000470615.1	M0QZK8
	GGCT	ENST00000005374.10	TSL:1	c.*7T>A		3_prime_UTR	Exon 3 of 3	ENSP00000005374.6	O75223-2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1458578 Hom.: 0 Cov.: 28 AF XY: 0.00000551 AC XY: 4 AN XY: 725818

African (AFR) AF: 0.000210 AC: 7 AN: 33358

American (AMR) AF: 0.00 AC: 0 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 86038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109554

Other (OTH) AF: 0.00 AC: 0 AN: 60244

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152138 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74312

African (AFR) AF: 0.000169 AC: 7 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

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	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	26
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.023	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.5
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.60		Gain of solvent accessibility (P = 0.0068)
MVP		0.74
MPC		1.3
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.89
gMVP		0.87
Mutation Taster		=16/84	disease causing

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: rs913404919; hg19: chr7-30536787;