14-77328554-G-A

Variant names:

• chr14-77328554-G-A
• rs8177565
• NM_145870.3:c.342+517G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_145870.3(GSTZ1):​c.342+517G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 172,398 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.018 (45 hom., cov: 33)
  • Exomes 𝑓: 0.020 (8 hom.)
• Consequence: GSTZ1 NM_145870.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.362
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.018 (2739/152328) while in subpopulation SAS AF = 0.0413 (199/4824). AF 95% confidence interval is 0.0366. There are 45 homozygotes in GnomAd4. There are 1346 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSTZ1	NM_145870.3	MANE Select	c.342+517G>A		intron	N/A	NP_665877.1
	GSTZ1	NM_001363703.2		c.345+517G>A		intron	N/A	NP_001350632.1
	GSTZ1	NM_145871.3		c.217-569G>A		intron	N/A	NP_665878.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSTZ1	ENST00000216465.10	TSL:1 MANE Select	c.342+517G>A		intron	N/A	ENSP00000216465.5
	GSTZ1	ENST00000361389.8	TSL:1	c.177+517G>A		intron	N/A	ENSP00000354959.4
	GSTZ1	ENST00000555208.1	TSL:2	n.115G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2746 AN: 152210 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.00453

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.0573

Gnomad EAS AF: 0.0189

Gnomad SAS AF: 0.0418

Gnomad FIN AF: 0.0155

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0224

Gnomad OTH AF: 0.0315

GnomAD4 exome AF: 0.0201 AC: 404 AN: 20070 Hom.: 8 Cov.: 0 AF XY: 0.0219 AC XY: 221 AN XY: 10106

African (AFR) AF: 0.00296 AC: 1 AN: 338

American (AMR) AF: 0.0261 AC: 62 AN: 2376

Ashkenazi Jewish (ASJ) AF: 0.0385 AC: 14 AN: 364

East Asian (EAS) AF: 0.00458 AC: 4 AN: 874

South Asian (SAS) AF: 0.0335 AC: 62 AN: 1850

European-Finnish (FIN) AF: 0.00923 AC: 5 AN: 542

Middle Eastern (MID) AF: 0.0625 AC: 5 AN: 80

European-Non Finnish (NFE) AF: 0.0181 AC: 228 AN: 12612

Other (OTH) AF: 0.0222 AC: 23 AN: 1034

GnomAD4 genome AF: 0.0180 AC: 2739 AN: 152328 Hom.: 45 Cov.: 33 AF XY: 0.0181 AC XY: 1346 AN XY: 74496

African (AFR) AF: 0.00450 AC: 187 AN: 41578

American (AMR) AF: 0.0185 AC: 283 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0573 AC: 199 AN: 3472

East Asian (EAS) AF: 0.0187 AC: 97 AN: 5186

South Asian (SAS) AF: 0.0413 AC: 199 AN: 4824

European-Finnish (FIN) AF: 0.0155 AC: 165 AN: 10620

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0224 AC: 1521 AN: 68028

Other (OTH) AF: 0.0307 AC: 65 AN: 2116

Alfa AF: 0.0199 Hom.: 5

Bravo AF: 0.0166

Asia WGS AF: 0.0200 AC: 71 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.67
DANN	Benign	0.63
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism

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: rs8177565; hg19: chr14-77794897;