1-109715203-C-T

Position:

• chr1-109715203-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000851.4(GSTM5):​c.530C>T​(p.Ala177Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,614,110 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: GSTM5 NM_000851.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13

Genes affected

GSTM5 (HGNC:4637): (glutathione S-transferase mu 5) Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-transferase that belongs to the mu class. The mu class of enzymes functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding the mu class of enzymes are organized in a gene cluster on chromosome 1p13.3 and are known to be highly polymorphic. These genetic variations can change an individual's susceptibility to carcinogens and toxins as well as affect the toxicity and efficacy of certain drugs. Diversification of these genes has occurred in regions encoding substrate-binding domains, as well as in tissue expression patterns, to accommodate an increasing number of foreign compounds. [provided by RefSeq, Jul 2008]

GSTM5 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09560603).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSTM5	NM_000851.4	c.530C>T	p.Ala177Val	missense_variant	7/8	ENST00000256593.8	NP_000842.2
GSTM5	XM_005270784.5	c.530C>T	p.Ala177Val	missense_variant	8/9		XP_005270841.1
GSTM5	XM_005270785.5	c.218C>T	p.Ala73Val	missense_variant	4/5		XP_005270842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSTM5	ENST00000256593.8	c.530C>T	p.Ala177Val	missense_variant	7/8	1	NM_000851.4	ENSP00000256593.3

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000119 AC: 30 AN: 251476 Hom.: 0 AF XY: 0.000132 AC XY: 18 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000196 AC: 287 AN: 1461886 Hom.: 1 Cov.: 31 AF XY: 0.000223 AC XY: 162 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000672

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000192

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74362

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.0000567

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2023

The c.530C>T (p.A177V) alteration is located in exon 7 (coding exon 7) of the GSTM5 gene. This alteration results from a C to T substitution at nucleotide position 530, causing the alanine (A) at amino acid position 177 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.011	.;T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.096	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	3.1	.;M;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.1	.;N;.
REVEL	Benign	0.076
Sift	Benign	0.22	.;T;.
Sift4G	Benign	0.26	.;T;T
Polyphen		0.048	.;B;.
Vest4		0.17, 0.24
MVP		0.12
MPC		0.11
ClinPred		0.089	T
GERP RS		2.8
Varity_R		0.18
gMVP		0.11

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: rs376313197; hg19: chr1-110257825; COSMIC: COSV105848405;