1-109688178-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000561.4(GSTM1):c.45C>A(p.His15Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (5 hom., cov: 13)
  • Exomes 𝑓: 0.00042 (116 hom.)
• Consequence: GSTM1 NM_000561.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.388

Genes affected

GSTM1 (HGNC:4632): (glutathione S-transferase mu 1) 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. Null mutations of this class mu gene have been linked with an increase in a number of cancers, likely due to an increased susceptibility to environmental toxins and carcinogens. Multiple protein isoforms are encoded by transcript variants of this gene. [provided by RefSeq, Jul 2008]

GSTM2 (HGNC:4634): (glutathione S-transferase mu 2) 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056289732).
• BP6: Variant 1-109688178-C-A is Benign according to our data. Variant chr1-109688178-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 754642.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-109688178-C-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSTM1	NM_000561.4	c.45C>A	p.His15Gln	missense_variant	2/8	ENST00000309851.10
GSTM1	NM_146421.3	c.45C>A	p.His15Gln	missense_variant	2/7
GSTM1	XM_005270782.6	c.-58C>A		5_prime_UTR_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSTM1	ENST00000309851.10	c.45C>A	p.His15Gln	missense_variant	2/8	1	NM_000561.4	P1

Frequencies

GnomAD3 genomes AF: 0.000121 AC: 10 AN: 82564 Hom.: 5 Cov.: 13

Gnomad AFR AF: 0.0000688

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00215

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000630

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000921 AC: 122 AN: 132486 Hom.: 49 AF XY: 0.00117 AC XY: 83 AN XY: 71184

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000518

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000240

Gnomad OTH exome AF: 0.00128

GnomAD4 exome AF: 0.000415 AC: 297 AN: 715554 Hom.: 116 Cov.: 0 AF XY: 0.000571 AC XY: 204 AN XY: 357504

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000399

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00433

Gnomad4 FIN exome AF: 0.0000691

Gnomad4 NFE exome AF: 0.0000806

Gnomad4 OTH exome AF: 0.000900

GnomAD4 genome AF: 0.000121 AC: 10 AN: 82680 Hom.: 5 Cov.: 13 AF XY: 0.000149 AC XY: 6 AN XY: 40382

Gnomad4 AFR AF: 0.0000685

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00216

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000630

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000169 Hom.: 1

ExAC AF: 0.000829 AC: 63

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jun 23, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	18
Dann	Benign	0.88
DEOGEN2	Benign	0.15	T;T;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.045	N
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.0056	T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.51	N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.6	D;D;D;D;D
REVEL	Benign	0.074
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		1.0	D;.;B;.;.
Vest4		0.45
MutPred		0.58		Gain of MoRF binding (P = 0.0974);Gain of MoRF binding (P = 0.0974);Gain of MoRF binding (P = 0.0974);Gain of MoRF binding (P = 0.0974);Gain of MoRF binding (P = 0.0974);
MVP		0.23
MPC		1.4
ClinPred		0.038	T
GERP RS		-4.1
Varity_R		0.28
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs567320393; hg19: chr1-110230800;