chr14-77326894-G-A

Position:

• chr14-77326894-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_145870.3(GSTZ1):​c.124G>A​(p.Gly42Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0808 in 1,600,028 control chromosomes in the GnomAD database, including 6,542 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (620 hom., cov: 33)
  • Exomes 𝑓: 0.082 (5922 hom.)
• Consequence: GSTZ1 NM_145870.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.22

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016635954).
• BP6: Variant 14-77326894-G-A is Benign according to our data. Variant chr14-77326894-G-A is described in ClinVar as [Benign]. Clinvar id is 1234080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSTZ1	NM_145870.3	c.124G>A	p.Gly42Arg	missense_variant	3/9	ENST00000216465.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSTZ1	ENST00000216465.10	c.124G>A	p.Gly42Arg	missense_variant	3/9	1	NM_145870.3

Frequencies

GnomAD3 genomes AF: 0.0686 AC: 10446 AN: 152220 Hom.: 620 Cov.: 33

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.0402

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0223

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0947

Gnomad OTH AF: 0.0612

GnomAD3 exomes AF: 0.0700 AC: 16439 AN: 234830 Hom.: 955 AF XY: 0.0696 AC XY: 8819 AN XY: 126684

Gnomad AFR exome AF: 0.0122

Gnomad AMR exome AF: 0.0300

Gnomad ASJ exome AF: 0.0440

Gnomad EAS exome AF: 0.0000562

Gnomad SAS exome AF: 0.0244

Gnomad FIN exome AF: 0.213

Gnomad NFE exome AF: 0.0893

Gnomad OTH exome AF: 0.0775

GnomAD4 exome AF: 0.0821 AC: 118870 AN: 1447690 Hom.: 5922 Cov.: 29 AF XY: 0.0807 AC XY: 58040 AN XY: 719280

Gnomad4 AFR exome AF: 0.0111

Gnomad4 AMR exome AF: 0.0313

Gnomad4 ASJ exome AF: 0.0452

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.0259

Gnomad4 FIN exome AF: 0.212

Gnomad4 NFE exome AF: 0.0889

Gnomad4 OTH exome AF: 0.0735

GnomAD4 genome AF: 0.0686 AC: 10443 AN: 152338 Hom.: 620 Cov.: 33 AF XY: 0.0717 AC XY: 5343 AN XY: 74488

Gnomad4 AFR AF: 0.0145

Gnomad4 AMR AF: 0.0402

Gnomad4 ASJ AF: 0.0507

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.210

Gnomad4 NFE AF: 0.0947

Gnomad4 OTH AF: 0.0605

Alfa AF: 0.0794 Hom.: 1381

Bravo AF: 0.0531

TwinsUK AF: 0.0965 AC: 358

ALSPAC AF: 0.0908 AC: 350

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.0822 AC: 707

ExAC AF: 0.0657 AC: 7970

Asia WGS AF: 0.0140 AC: 49 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2019	This variant is associated with the following publications: (PMID: 10739172, 25525159, 19252927) -

GSTZ1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.075	.;T;T;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	D;D;D;D;D
MetaRNN	Benign	0.0017	T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0e-8	P;P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.9	D;D;D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0070	D;D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D
Vest4		0.21
MutPred		0.45		Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);.;
MPC		0.067
ClinPred		0.026	T
GERP RS		5.6
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs7972; hg19: chr14-77793237; COSMIC: COSV53623470; COSMIC: COSV53623470;