14-77326864-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.94G>A(p.Glu32Lys) variant causes a missense change. The variant allele was found at a frequency of 0.32 in 1,602,590 control chromosomes in the GnomAD database, including 83,900 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (7778 hom., cov: 33)
  • Exomes 𝑓: 0.32 (76122 hom.)
• Consequence: GSTZ1 NM_145870.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.23

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=0.0017864704).
• BP6: Variant 14-77326864-G-A is Benign according to our data. Variant chr14-77326864-G-A is described in ClinVar as [Benign]. Clinvar id is 1251643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSTZ1	NM_145870.3	c.94G>A	p.Glu32Lys	missense_variant	3/9	ENST00000216465.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSTZ1	ENST00000216465.10	c.94G>A	p.Glu32Lys	missense_variant	3/9	1	NM_145870.3

Frequencies

GnomAD3 genomes AF: 0.316 AC: 48040 AN: 152028 Hom.: 7764 Cov.: 33

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.457

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.295

GnomAD3 exomes AF: 0.307 AC: 73131 AN: 238540 Hom.: 11752 AF XY: 0.304 AC XY: 39187 AN XY: 128836

Gnomad AFR exome AF: 0.297

Gnomad AMR exome AF: 0.204

Gnomad ASJ exome AF: 0.326

Gnomad EAS exome AF: 0.452

Gnomad SAS exome AF: 0.214

Gnomad FIN exome AF: 0.388

Gnomad NFE exome AF: 0.323

Gnomad OTH exome AF: 0.315

GnomAD4 exome AF: 0.320 AC: 464016 AN: 1450444 Hom.: 76122 Cov.: 31 AF XY: 0.317 AC XY: 228578 AN XY: 720864

Gnomad4 AFR exome AF: 0.295

Gnomad4 AMR exome AF: 0.206

Gnomad4 ASJ exome AF: 0.334

Gnomad4 EAS exome AF: 0.489

Gnomad4 SAS exome AF: 0.219

Gnomad4 FIN exome AF: 0.390

Gnomad4 NFE exome AF: 0.324

Gnomad4 OTH exome AF: 0.319

GnomAD4 genome AF: 0.316 AC: 48070 AN: 152146 Hom.: 7778 Cov.: 33 AF XY: 0.315 AC XY: 23435 AN XY: 74362

Gnomad4 AFR AF: 0.298

Gnomad4 AMR AF: 0.231

Gnomad4 ASJ AF: 0.340

Gnomad4 EAS AF: 0.459

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.393

Gnomad4 NFE AF: 0.328

Gnomad4 OTH AF: 0.301

Alfa AF: 0.323 Hom.: 15067

Bravo AF: 0.304

TwinsUK AF: 0.332 AC: 1231

ALSPAC AF: 0.322 AC: 1242

ESP6500AA AF: 0.295 AC: 1299

ESP6500EA AF: 0.327 AC: 2814

ExAC AF: 0.300 AC: 36415

Asia WGS AF: 0.345 AC: 1195 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GSTZ1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 16, 2020

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 2019

This variant is associated with the following publications: (PMID: 22374552) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.44
Cadd	Uncertain	24
Dann	Pathogenic	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;D;D;D;T
MetaRNN	Benign	0.0018	T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	2.1e-7	P;P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.027	D;D;D;D;D
Sift4G	Benign	0.092	T;T;T;T;T
Vest4		0.22
MPC		0.059
ClinPred		0.017	T
GERP RS		5.6
gMVP		0.70

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

Other links and lift over

dbSNP: rs7975; hg19: chr14-77793207; COSMIC: COSV99374352; COSMIC: COSV99374352;