Genetic Variant GSTM4:p.Ter219Ter (chr1-109661254-A-G) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBP7

The NM_000850.5(GSTM4):c.657A>G(p.Ter219Ter) variant causes a stop retained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0029 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 101 hom. )

Failed GnomAD Quality Control

Consequence

GSTM4
NM_000850.5 stop_retained

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.419

Publications

0 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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 1-109661254-A-G is Benign according to our data. Variant chr1-109661254-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2858562.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.419 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000850.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GSTM4	NM_000850.5	MANE Select	c.657A>G	p.Ter219Ter	stop_retained	Exon 8 of 8	NP_000841.1	A0A140VKE3
GSTM4	NM_147148.3		c.567+2144A>G		intron	N/A	NP_671489.1	Q03013-2
GSTM4	NR_024538.2		n.866A>G		non_coding_transcript_exon	Exon 7 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GSTM4	ENST00000369836.9	TSL:1 MANE Select	c.657A>G	p.Ter219Ter	stop_retained	Exon 8 of 8	ENSP00000358851.4	Q03013-1
GSTM4	ENST00000326729.9	TSL:1	c.567+2144A>G		intron	N/A	ENSP00000316471.5	Q03013-2
GSTM4	ENST00000495742.5	TSL:1	n.713A>G		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes

AF:

0.00291

AC:

417

AN:

143058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00877

Gnomad AMI

AF:

0.00117

Gnomad AMR

AF:

0.00148

Gnomad ASJ

AF:

0.000583

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00108

Gnomad OTH

AF:

0.00499

GnomAD2 exomes

AF:

0.000361

AC:

AN:

248984

AF XY:

0.000363

show subpopulations

Gnomad AFR exome

AF:

0.00308

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000248

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000418

AC:

602

AN:

1440950

Hom.:

101

Cov.:

AF XY:

0.000403

AC XY:

289

AN XY:

717656

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00527

AC:

156

AN:

29620

American (AMR)

AF:

0.0000900

AC:

AN:

44448

Ashkenazi Jewish (ASJ)

AF:

0.000231

AC:

AN:

25946

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39692

South Asian (SAS)

AF:

0.000336

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.000352

AC:

386

AN:

1096646

Other (OTH)

AF:

0.000286

AC:

AN:

59358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.326

Heterozygous variant carriers

122

163

204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00291

AC:

417

AN:

143176

Hom.:

Cov.:

AF XY:

0.00292

AC XY:

205

AN XY:

70224

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00880

AC:

302

AN:

34336

American (AMR)

AF:

0.00141

AC:

AN:

14850

Ashkenazi Jewish (ASJ)

AF:

0.000583

AC:

AN:

3430

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000378

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00108

AC:

AN:

66804

Other (OTH)

AF:

0.00494

AC:

AN:

2026

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.263

Heterozygous variant carriers

104

156

208

260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00498

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

7.8

(source)

DANN

Benign

0.58

PhyloP100

0.42

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over