NM_145870.3:c.94G>A

Variant names:

• chr14-77326864-G-A
• rs7975
• NM_145870.3:c.94G>A

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 5.23
• Publications: 72 publications found

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 Gene-Disease associations (from GenCC):

• maleylacetoacetate isomerase deficiency

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145870.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSTZ1	NM_145870.3	MANE Select	c.94G>A	p.Glu32Lys	missense	Exon 3 of 9	NP_665877.1	A0A0C4DFM0
	GSTZ1	NM_001363703.2		c.97G>A	p.Glu33Lys	missense	Exon 3 of 9	NP_001350632.1	G3V4T6
	GSTZ1	NM_145871.3		c.94G>A	p.Glu32Lys	missense	Exon 3 of 8	NP_665878.2	A0A0A0MR33

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSTZ1	ENST00000216465.10	TSL:1 MANE Select	c.94G>A	p.Glu32Lys	missense	Exon 3 of 9	ENSP00000216465.5	A0A0C4DFM0
	GSTZ1	ENST00000361389.8	TSL:1	c.-72G>A		5_prime_UTR	Exon 4 of 10	ENSP00000354959.4	O43708-2
	GSTZ1	ENST00000553838.5	TSL:1	n.264G>A		non_coding_transcript_exon	Exon 3 of 4

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

GnomAD2 exomes AF: 0.307 AC: 73131 AN: 238540 AF XY: 0.304

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 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

African (AFR) AF: 0.295 AC: 9839 AN: 33358

American (AMR) AF: 0.206 AC: 9012 AN: 43832

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 8642 AN: 25906

East Asian (EAS) AF: 0.489 AC: 19327 AN: 39560

South Asian (SAS) AF: 0.219 AC: 18528 AN: 84790

European-Finnish (FIN) AF: 0.390 AC: 20623 AN: 52830

Middle Eastern (MID) AF: 0.245 AC: 1410 AN: 5750

European-Non Finnish (NFE) AF: 0.324 AC: 357515 AN: 1104438

Other (OTH) AF: 0.319 AC: 19120 AN: 59980

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

African (AFR) AF: 0.298 AC: 12378 AN: 41502

American (AMR) AF: 0.231 AC: 3525 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1181 AN: 3472

East Asian (EAS) AF: 0.459 AC: 2374 AN: 5170

South Asian (SAS) AF: 0.234 AC: 1128 AN: 4818

European-Finnish (FIN) AF: 0.393 AC: 4163 AN: 10584

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.328 AC: 22333 AN: 67992

Other (OTH) AF: 0.301 AC: 635 AN: 2110

Alfa AF: 0.312 Hom.: 23811

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	GSTZ1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.082	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.90	T
PhyloP100		5.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.27
Sift	Uncertain	0.027	D
Sift4G	Benign	0.092	T
Vest4		0.22
MPC		0.059
ClinPred		0.017	T
GERP RS		5.6
gMVP		0.70
Mutation Taster		=154/146	polymorphism (auto)

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

Other links and lift over

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