1-109688178-C-A

Position:

chr1-109688178-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

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

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.388

Variant links:

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]

GSTM1 links:

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]

GSTM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 5 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSTM1	ENST00000309851.10 linkuse as main transcript	c.45C>A	p.His15Gln	missense_variant	2/8	1	NM_000561.4	P1	P09488-1

Frequencies

GnomAD3 genomes

AF:

0.000121

AC:

AN:

82564

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00117

AC XY:

AN XY:

71184

show subpopulations

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.:

AF XY:

0.000571

AC XY:

204

AN XY:

357504

show subpopulations

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:

AN:

82680

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

40382

show subpopulations

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.:

ExAC

AF:

0.000829

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.15

T;T;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.045

LIST_S2

Uncertain

0.88

D;D;D;D;D

M_CAP

Benign

0.0014

MetaRNN

Benign

0.0056

T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.51

N;.;N;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Uncertain

0.75

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over