Genetic Variant GGT5:p.Ala519Ser (chr22-24225055-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004121.5(GGT5):c.1555G>T(p.Ala519Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,449,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A519T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GGT5
NM_004121.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.187

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33873993).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004121.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GGT5	NM_004121.5	MANE Select	c.1555G>T	p.Ala519Ser	missense	Exon 11 of 12	NP_004112.2	P36269-1
GGT5	NM_001099781.2		c.1558G>T	p.Ala520Ser	missense	Exon 11 of 12	NP_001093251.1	P36269-3
GGT5	NM_001099782.2		c.1459G>T	p.Ala487Ser	missense	Exon 10 of 11	NP_001093252.1	P36269-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GGT5	ENST00000327365.10	TSL:1 MANE Select	c.1555G>T	p.Ala519Ser	missense	Exon 11 of 12	ENSP00000330080.4	P36269-1
GGT5	ENST00000398292.3	TSL:1	c.1558G>T	p.Ala520Ser	missense	Exon 11 of 12	ENSP00000381340.3	P36269-3
GGT5	ENST00000263112.11	TSL:1	c.1459G>T	p.Ala487Ser	missense	Exon 10 of 11	ENSP00000263112.7	P36269-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1449312

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

720036

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33102

American (AMR)

AF:

0.00

AC:

AN:

42988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25822

East Asian (EAS)

AF:

0.0000514

AC:

AN:

38894

South Asian (SAS)

AF:

0.00

AC:

AN:

84548

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106090

Other (OTH)

AF:

0.0000167

AC:

AN:

59852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.051

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.65

M_CAP

Benign

0.013

MetaRNN

Benign

0.34

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

-0.19

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.98

REVEL

Benign

0.037

Sift

Benign

0.46

Sift4G

Benign

0.43

Polyphen

0.036

Vest4

0.16

MutPred

0.65

Loss of stability (P = 0.1262)

MVP

0.46

MPC

0.21

ClinPred

0.22

GERP RS

2.3

Varity_R

0.062

gMVP

0.64

Mutation Taster

=80/20

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over