ENST00000005374.10:c.323G>A

Variant names:

• chr7-30497200-C-T
• rs115910467
• ENST00000005374.10:c.323G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000005374.10(GGCT):​c.323G>A​(p.Arg108His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000796 in 1,610,802 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (2 hom.)
• Consequence: GGCT ENST00000005374.10 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.421
• Publications: 21 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024662912).
• BP6: Variant 7-30497200-C-T is Benign according to our data. Variant chr7-30497200-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 711870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000005374.10. 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.459G>A	p.Pro153Pro	synonymous	Exon 4 of 4	NP_076956.1	O75223-1
	GGCT	NM_001199815.2		c.479G>A	p.Arg160His	missense	Exon 4 of 4	NP_001186744.1	O75223-4
	GGCT	NM_001199816.2		c.323G>A	p.Arg108His	missense	Exon 3 of 3	NP_001186745.1	O75223-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGCT	ENST00000005374.10	TSL:1	c.323G>A	p.Arg108His	missense	Exon 3 of 3	ENSP00000005374.6	O75223-2
	GGCT	ENST00000275428.9	TSL:1 MANE Select	c.459G>A	p.Pro153Pro	synonymous	Exon 4 of 4	ENSP00000275428.4	O75223-1
	ENSG00000281039	ENST00000598361.4	TSL:5	c.204G>A	p.Pro68Pro	synonymous	Exon 5 of 5	ENSP00000470615.1	M0QZK8

Frequencies

GnomAD3 genomes AF: 0.00305 AC: 464 AN: 152110 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00949

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000941 AC: 232 AN: 246608 AF XY: 0.000779

Gnomad AFR exome AF: 0.00888

Gnomad AMR exome AF: 0.000709

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000560 AC: 817 AN: 1458574 Hom.: 2 Cov.: 29 AF XY: 0.000531 AC XY: 385 AN XY: 725660

African (AFR) AF: 0.00956 AC: 318 AN: 33254

American (AMR) AF: 0.000993 AC: 44 AN: 44302

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26086

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39588

South Asian (SAS) AF: 0.000362 AC: 31 AN: 85714

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53286

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5760

European-Non Finnish (NFE) AF: 0.000299 AC: 332 AN: 1110364

Other (OTH) AF: 0.00103 AC: 62 AN: 60220

GnomAD4 genome AF: 0.00306 AC: 466 AN: 152228 Hom.: 2 Cov.: 33 AF XY: 0.00302 AC XY: 225 AN XY: 74434

African (AFR) AF: 0.00951 AC: 395 AN: 41516

American (AMR) AF: 0.00261 AC: 40 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4816

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68020

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00117 Hom.: 2

Bravo AF: 0.00395

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00101 AC: 122

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000656

EpiControl AF: 0.000476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	2.3
DANN	Benign	0.71
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0076	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.42
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.15
Sift	Benign	0.90	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.032
MVP		0.22
ClinPred		0.013	T
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs115910467; hg19: chr7-30536816;