1-109715192-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000851.4(GSTM5):c.519G>C(p.Lys173Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,614,196 control chromosomes in the GnomAD database, including 135 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (127 hom.)
• Consequence: GSTM5 NM_000851.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.400

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006391436).
• BP6: Variant 1-109715192-G-C is Benign according to our data. Variant chr1-109715192-G-C is described in ClinVar as [Benign]. Clinvar id is 779857.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSTM5	NM_000851.4	c.519G>C	p.Lys173Asn	missense_variant	7/8	ENST00000256593.8
GSTM5	XM_005270784.5	c.519G>C	p.Lys173Asn	missense_variant	8/9
GSTM5	XM_005270785.5	c.207G>C	p.Lys69Asn	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSTM5	ENST00000256593.8	c.519G>C	p.Lys173Asn	missense_variant	7/8	1	NM_000851.4	P3

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 432 AN: 152190 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0675

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00598 AC: 1504 AN: 251496 Hom.: 64 AF XY: 0.00530 AC XY: 721 AN XY: 135922

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0773

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00241 AC: 3530 AN: 1461888 Hom.: 127 Cov.: 31 AF XY: 0.00232 AC XY: 1685 AN XY: 727246

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0764

Gnomad4 SAS exome AF: 0.00155

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000522

Gnomad4 OTH exome AF: 0.00474

GnomAD4 genome AF: 0.00286 AC: 436 AN: 152308 Hom.: 8 Cov.: 33 AF XY: 0.00314 AC XY: 234 AN XY: 74482

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0680

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000357 Hom.: 0

Bravo AF: 0.00340

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00586 AC: 712

Asia WGS AF: 0.0360 AC: 127 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	1.5
Dann	Benign	0.85
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.23	T;T;T
MetaRNN	Benign	0.0064	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
Polyphen		0.0010	.;B;.
Vest4		0.40, 0.43
MutPred		0.25		Loss of methylation at K173 (P = 0.004);Loss of methylation at K173 (P = 0.004);Loss of methylation at K173 (P = 0.004);
MVP		0.076
MPC		0.14
ClinPred		0.0087	T
GERP RS		-0.56
Varity_R		0.14
gMVP		0.17

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: rs78955679; hg19: chr1-110257814; COSMIC: COSV56657134;