14-77327940-T-C

Variant names:

• chr14-77327940-T-C
• rs1046428
• NM_145870.3:c.245T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_145870.3(GSTZ1):​c.245T>C​(p.Met82Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.804 in 1,613,244 control chromosomes in the GnomAD database, including 523,055 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M82I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.83 (52981 hom., cov: 30)
  • Exomes 𝑓: 0.80 (470074 hom.)
• Consequence: GSTZ1 NM_145870.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.44

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.2019495E-7).
• BP6: Variant 14-77327940-T-C is Benign according to our data. Variant chr14-77327940-T-C is described in ClinVar as [Benign]. Clinvar id is 2663453.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.931 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSTZ1	NM_145870.3	c.245T>C	p.Met82Thr	missense_variant	Exon 5 of 9	ENST00000216465.10	NP_665877.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSTZ1	ENST00000216465.10	c.245T>C	p.Met82Thr	missense_variant	Exon 5 of 9	1	NM_145870.3	ENSP00000216465.5

Frequencies

GnomAD3 genomes AF: 0.833 AC: 126469 AN: 151892 Hom.: 52937 Cov.: 30

Gnomad AFR AF: 0.901

Gnomad AMI AF: 0.876

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.831

Gnomad EAS AF: 0.953

Gnomad SAS AF: 0.792

Gnomad FIN AF: 0.871

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.798

Gnomad OTH AF: 0.833

GnomAD2 exomes AF: 0.813 AC: 204080 AN: 251120 AF XY: 0.810

Gnomad AFR exome AF: 0.907

Gnomad AMR exome AF: 0.722

Gnomad ASJ exome AF: 0.822

Gnomad EAS exome AF: 0.963

Gnomad FIN exome AF: 0.854

Gnomad NFE exome AF: 0.802

Gnomad OTH exome AF: 0.807

GnomAD4 exome AF: 0.801 AC: 1170336 AN: 1461234 Hom.: 470074 Cov.: 44 AF XY: 0.801 AC XY: 582033 AN XY: 726960

Gnomad4 AFR exome AF: 0.912 AC: 30519 AN: 33476

Gnomad4 AMR exome AF: 0.733 AC: 32752 AN: 44708

Gnomad4 ASJ exome AF: 0.822 AC: 21482 AN: 26134

Gnomad4 EAS exome AF: 0.966 AC: 38368 AN: 39698

Gnomad4 SAS exome AF: 0.781 AC: 67380 AN: 86246

Gnomad4 FIN exome AF: 0.853 AC: 45506 AN: 53364

Gnomad4 NFE exome AF: 0.792 AC: 880704 AN: 1111468

Gnomad4 Remaining exome AF: 0.813 AC: 49088 AN: 60372

GnomAD4 genome AF: 0.833 AC: 126569 AN: 152010 Hom.: 52981 Cov.: 30 AF XY: 0.834 AC XY: 61994 AN XY: 74292

Gnomad4 AFR AF: 0.901 AC: 0.901361 AN: 0.901361

Gnomad4 AMR AF: 0.743 AC: 0.743059 AN: 0.743059

Gnomad4 ASJ AF: 0.831 AC: 0.831221 AN: 0.831221

Gnomad4 EAS AF: 0.954 AC: 0.95366 AN: 0.95366

Gnomad4 SAS AF: 0.792 AC: 0.79158 AN: 0.79158

Gnomad4 FIN AF: 0.871 AC: 0.870962 AN: 0.870962

Gnomad4 NFE AF: 0.798 AC: 0.798231 AN: 0.798231

Gnomad4 OTH AF: 0.835 AC: 0.835389 AN: 0.835389

Alfa AF: 0.810 Hom.: 242836

Bravo AF: 0.828

TwinsUK AF: 0.789 AC: 2925

ALSPAC AF: 0.782 AC: 3013

ESP6500AA AF: 0.901 AC: 3972

ESP6500EA AF: 0.805 AC: 6921

ExAC AF: 0.816 AC: 99079

Asia WGS AF: 0.879 AC: 3060 AN: 3478

EpiCase AF: 0.793

EpiControl AF: 0.794

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

GSTZ1-related disorder Benign:1

Mar 16, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Oct 30, 2023

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Benign	0.56
DEOGEN2	Benign	0.0026	.;.;T;.;.;T;.;.;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.49	T;.;T;.;T;T;T;T;T
MetaRNN	Benign	6.2e-7	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	4.2	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.090
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T
Vest4		0.051
MPC		0.054
ClinPred		0.0045	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.70
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1046428; hg19: chr14-77794283; COSMIC: COSV107243421; COSMIC: COSV107243421;