chr14-77327990-G-A

Position:

chr14-77327990-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PS1_ModeratePP5_ModerateBP4BS2_Supporting

The NM_145870.3(GSTZ1):c.295G>A(p.Val99Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00073 in 1,614,066 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00076 ( 4 hom. )

Consequence

GSTZ1
NM_145870.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1U:1O:1

Conservation

PhyloP100: 7.23

Variant links:

Genes affected

GSTZ1 (HGNC:4643): (glutathione S-transferase zeta 1) This gene is a member of the glutathione S-transferase (GSTs) super-family which encodes multifunctional enzymes important in the detoxification of electrophilic molecules, including carcinogens, mutagens, and several therapeutic drugs, by conjugation with glutathione. This enzyme catalyzes the conversion of maleylacetoacetate to fumarylacetoacatate, which is one of the steps in the phenylalanine/tyrosine degradation pathway. Deficiency of a similar gene in mouse causes oxidative stress. Several transcript variants of this gene encode multiple protein isoforms. [provided by RefSeq, Jul 2015]

GSTZ1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PS1

Transcript NM_145870.3 (GSTZ1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PP5

Variant 14-77327990-G-A is Pathogenic according to our data. Variant chr14-77327990-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431044.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.15578839). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 4 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSTZ1	NM_145870.3 linkuse as main transcript	c.295G>A	p.Val99Met	missense_variant	5/9	ENST00000216465.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSTZ1	ENST00000216465.10 linkuse as main transcript	c.295G>A	p.Val99Met	missense_variant	5/9	1	NM_145870.3

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

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:

0.000808

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000502

AC:

126

AN:

251144

Hom.:

AF XY:

0.000508

AC XY:

AN XY:

135762

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000756

AC:

1105

AN:

1461750

Hom.:

Cov.:

AF XY:

0.000708

AC XY:

515

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000963

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000479

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000809

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000769

Hom.:

Bravo

AF:

0.000461

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000527

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.00113

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2022

GSTZ1: PM2, PP4:Moderate, PM3:Supporting, PS3:Supporting -

GSTZ1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2024

The GSTZ1 c.295G>A variant is predicted to result in the amino acid substitution p.Val99Met. This variant has been reported in the heterozygous state in a newborn with elevated succinylacetone in the blood (Yang et al. 2016. PubMed ID: 27876694). In a bacterial expression assay, the p.Val99Met substitution was reported to mildly reduce the activity of the maleylacetoacetate isomerase enzyme (Yang et al. 2016. PubMed ID: 27876694). This variant is reported in 0.10% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including one homozygous individual. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Maleylacetoacetate isomerase deficiency

Other:1

Affects, no assertion criteria provided

literature only

OMIM

Jul 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.084

.;.;T;.;.;T;.;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.98

D;.;D;.;D;D;D;D

M_CAP

Benign

0.044

MetaRNN

Benign

0.16

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.23

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.5

D;D;D;D;D;N;D;D

REVEL

Uncertain

0.32

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.028

D;D;D;D;T;D;D;D

Vest4

0.62

MVP

0.79

MPC

0.23

ClinPred

0.23

GERP RS

4.8

gMVP

0.88

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