Genetic Variant GGT5:p.Arg514Lys (chr22-24225069-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004121.5(GGT5):c.1541G>A(p.Arg514Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000483 in 1,448,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

GGT5
NM_004121.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.229

Variant links:

Genes affected

GGT5 (HGNC:4260): (gamma-glutamyltransferase 5) This gene is a member of the gamma-glutamyl transpeptidase gene family, and some reports indicate that it is capable of cleaving the gamma-glutamyl moiety of glutathione. The protein encoded by this gene is synthesized as a single, catalytically-inactive polypeptide, that is processed post-transcriptionally to form a heavy and light subunit, with the catalytic activity contained within the small subunit. The encoded enzyme is able to convert leukotriene C4 to leukotriene D4, but appears to have distinct substrate specificity compared to gamma-glutamyl transpeptidase. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2014]

GGT5 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.041546583).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGT5	NM_004121.5 link	c.1541G>A	p.Arg514Lys	missense_variant	Exon 11 of 12	ENST00000327365.10	NP_004112.2	P36269-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GGT5	ENST00000327365.10 link	c.1541G>A	p.Arg514Lys	missense_variant	Exon 11 of 12	1	NM_004121.5	ENSP00000330080.4	P36269-1
GGT5	ENST00000398292.3 link	c.1544G>A	p.Arg515Lys	missense_variant	Exon 11 of 12	1		ENSP00000381340.3	P36269-3
GGT5	ENST00000263112.11 link	c.1445G>A	p.Arg482Lys	missense_variant	Exon 10 of 11	1		ENSP00000263112.7	P36269-2
GGT5	ENST00000425408.5 link	c.347G>A	p.Arg116Lys	missense_variant	Exon 4 of 6	5		ENSP00000402917.1	H7C1X2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000440

AC:

AN:

227108

Hom.:

AF XY:

0.00

AC XY:

AN XY:

123202

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000985

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000483

AC:

AN:

1448916

Hom.:

Cov.:

AF XY:

0.00000556

AC XY:

AN XY:

719938

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.0000234

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000452

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1541G>A (p.R514K) alteration is located in exon 11 (coding exon 11) of the GGT5 gene. This alteration results from a G to A substitution at nucleotide position 1541, causing the arginine (R) at amino acid position 514 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

5.6

DANN

Benign

0.53

DEOGEN2

Benign

0.020

.;T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0024

LIST_S2

Benign

0.56

T;T;T

M_CAP

Benign

0.0042

MetaRNN

Benign

0.042

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.60

.;N;.

PrimateAI

Benign

0.22

PROVEAN

Benign

0.55

N;N;N

REVEL

Benign

0.065

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0020

B;B;.

Vest4

0.11

MutPred

0.53

.;Loss of methylation at R514 (P = 0.0332);.;

MVP

0.39

MPC

0.19

ClinPred

0.059

GERP RS

-9.1

Varity_R

0.036

gMVP

0.44

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

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