Genetic Variant GGCT:p.Arg108His (chr7-30497200-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001199815.2(GGCT):c.479G>A(p.Arg160His) 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. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0031 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00056 ( 2 hom. )

Consequence

GGCT
NM_001199815.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.421

Variant links:

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]

GGCT links:

ENSG00000281039 (HGNC:):

ENSG00000281039 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 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]. Clinvar id is 711870.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGCT	NM_024051.4 link	c.459G>A	p.Pro153Pro	synonymous_variant	Exon 4 of 4	ENST00000275428.9	NP_076956.1	O75223-1A0A090N7V5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGCT	ENST00000275428.9 link	c.459G>A	p.Pro153Pro	synonymous_variant	Exon 4 of 4	1	NM_024051.4	ENSP00000275428.4		O75223-1
ENSG00000281039	ENST00000598361.4 link	c.204G>A	p.Pro68Pro	synonymous_variant	Exon 5 of 5	5		ENSP00000470615.1		M0QZK8

Frequencies

GnomAD3 genomes

AF:

0.00305

AC:

464

AN:

152110

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000941

AC:

232

AN:

246608

Hom.:

AF XY:

0.000779

AC XY:

104

AN XY:

133564

show subpopulations

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 SAS exome

AF:

0.000469

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.:

Cov.:

AF XY:

0.000531

AC XY:

385

AN XY:

725660

show subpopulations

Gnomad4 AFR exome

AF:

0.00956

Gnomad4 AMR exome

AF:

0.000993

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.000362

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.000299

Gnomad4 OTH exome

AF:

0.00103

GnomAD4 genome

AF:

0.00306

AC:

466

AN:

152228

Hom.:

Cov.:

AF XY:

0.00302

AC XY:

225

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00951

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00117

Hom.:

Bravo

AF:

0.00395

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00101

AC:

122

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000656

EpiControl

AF:

0.000476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 29, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.41

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

LIST_S2

Benign

0.34

T;T

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-1.1

PROVEAN

Benign

-0.13

N;N

REVEL

Benign

0.15

Sift

Benign

0.90

T;T

Sift4G

Benign

0.59

T;T

Polyphen

0.0

B;.

Vest4

0.032

MVP

0.22

ClinPred

0.013

GERP RS

-12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over