1-109661254-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_000850.5(GSTM4):c.657A>G(p.Ter219=) 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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.419

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]

ACMG classification

Verdict is Benign. Variant got -11 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 id is 2858562.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.419 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSTM4	NM_000850.5	c.657A>G	p.Ter219=	stop_retained_variant	8/8	ENST00000369836.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSTM4	ENST00000369836.9	c.657A>G	p.Ter219=	stop_retained_variant	8/8	1	NM_000850.5	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 417 AN: 143058 Hom.: 3 Cov.: 32 FAILED QC

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

GnomAD3 exomes AF: 0.000361 AC: 90 AN: 248984 Hom.: 20 AF XY: 0.000363 AC XY: 49 AN XY: 134830

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 SAS exome AF: 0.000294

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.: 31 AF XY: 0.000403 AC XY: 289 AN XY: 717656

Gnomad4 AFR exome AF: 0.00527

Gnomad4 AMR exome AF: 0.0000900

Gnomad4 ASJ exome AF: 0.000231

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000352

Gnomad4 OTH exome AF: 0.000286

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00291 AC: 417 AN: 143176 Hom.: 3 Cov.: 32 AF XY: 0.00292 AC XY: 205 AN XY: 70224

Gnomad4 AFR AF: 0.00880

Gnomad4 AMR AF: 0.00141

Gnomad4 ASJ AF: 0.000583

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.00108

Gnomad4 OTH AF: 0.00494

Alfa AF: 0.00498 Hom.: 10

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 12, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	7.8
Dann	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1063575; hg19: chr1-110203876;