1-109717418-A-G

Position:

• chr1-109717418-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000851.4(GSTM5):​c.649A>G​(p.Ser217Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00931 in 1,612,738 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (81 hom.)
• Consequence: GSTM5 NM_000851.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.533

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034254491).
• BP6: Variant 1-109717418-A-G is Benign according to our data. Variant chr1-109717418-A-G is described in ClinVar as [Benign]. Clinvar id is 713558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSTM5	NM_000851.4	c.649A>G	p.Ser217Gly	missense_variant	8/8	ENST00000256593.8	NP_000842.2
GSTM5	XM_005270784.5	c.649A>G	p.Ser217Gly	missense_variant	9/9		XP_005270841.1
GSTM5	XM_005270785.5	c.337A>G	p.Ser113Gly	missense_variant	5/5		XP_005270842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSTM5	ENST00000256593.8	c.649A>G	p.Ser217Gly	missense_variant	8/8	1	NM_000851.4	ENSP00000256593.3

Frequencies

GnomAD3 genomes AF: 0.00756 AC: 1151 AN: 152170 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0300

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00814 AC: 2046 AN: 251460 Hom.: 17 AF XY: 0.00841 AC XY: 1143 AN XY: 135900

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00441

Gnomad FIN exome AF: 0.0267

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00949 AC: 13863 AN: 1460450 Hom.: 81 Cov.: 29 AF XY: 0.00943 AC XY: 6849 AN XY: 726678

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.00288

Gnomad4 ASJ exome AF: 0.00149

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00471

Gnomad4 FIN exome AF: 0.0227

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.00698

GnomAD4 genome AF: 0.00756 AC: 1151 AN: 152288 Hom.: 9 Cov.: 32 AF XY: 0.00827 AC XY: 616 AN XY: 74466

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0300

Gnomad4 NFE AF: 0.0100

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00868 Hom.: 15

Bravo AF: 0.00538

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00782 AC: 949

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00834

EpiControl AF: 0.00895

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 26, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.8
DANN	Benign	0.89
DEOGEN2	Benign	0.0041	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.42	T;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.85	N;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.10
Sift	Benign	0.44	T;.
Sift4G	Benign	0.45	T;T
Polyphen		0.0	B;.
Vest4		0.036
MVP		0.067
MPC		0.098
ClinPred		0.0048	T
GERP RS		3.1
Varity_R		0.12
gMVP		0.10

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: rs113130058; hg19: chr1-110260040; COSMIC: COSV99859376;