dbSNP rs41283498: GSTM4:c.259+1G>A (chr1-109657672-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000850.5(GSTM4):c.259+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00255 in 1,614,260 control chromosomes in the GnomAD database, including 9 homozygotes. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 8 hom. )

Consequence

GSTM4
NM_000850.5 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.39

Publications

5 publications found

Variant links:

Genes affected

GSTM4 (HGNC:4636): (glutathione S-transferase mu 4) 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. Multiple transcript variants, each encoding a distinct protein isoform, have been identified. [provided by RefSeq, Jul 2008]

GSTM4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSTM4	NM_000850.5 link	c.259+1G>A		splice_donor_variant, intron_variant	Intron 4 of 7	ENST00000369836.9	NP_000841.1	Q03013-1A0A140VKE3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSTM4	ENST00000369836.9 link	c.259+1G>A		splice_donor_variant, intron_variant	Intron 4 of 7	1	NM_000850.5	ENSP00000358851.4		Q03013-1

Frequencies

GnomAD3 genomes

AF:

0.00159

AC:

242

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00273

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00181

AC:

456

AN:

251490

AF XY:

0.00185

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00115

Gnomad NFE exome

AF:

0.00300

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00265

AC:

3868

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00262

AC XY:

1908

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33480

American (AMR)

AF:

0.000581

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00314

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000881

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00165

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00309

AC:

3440

AN:

1112012

Other (OTH)

AF:

0.00225

AC:

136

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

250

500

750

1000

1250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00159

AC:

242

AN:

152368

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41588

American (AMR)

AF:

0.000980

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00273

AC:

186

AN:

68042

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00235

Hom.:

Bravo

AF:

0.00159

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00384

AC:

ExAC

AF:

0.00166

AC:

201

EpiCase

AF:

0.00284

EpiControl

AF:

0.00207

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.063

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.97

PhyloP100

6.4

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.30

Position offset: -3

DS_DL_spliceai

1.0

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over