3-9756791-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP4_Strong BP6_Very_Strong BS2

The NM_002542.6(OGG1):c.923G>A(p.Gly308Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00487 in 1,614,070 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (26 hom.)
• Consequence: OGG1 NM_002542.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 8.63

Genes affected

OGG1 (HGNC:8125): (8-oxoguanine DNA glycosylase) This gene encodes the enzyme responsible for the excision of 8-oxoguanine, a mutagenic base byproduct which occurs as a result of exposure to reactive oxygen. The action of this enzyme includes lyase activity for chain cleavage. Alternative splicing of the C-terminal region of this gene classifies splice variants into two major groups, type 1 and type 2, depending on the last exon of the sequence. Type 1 alternative splice variants end with exon 7 and type 2 end with exon 8. All variants share the N-terminal region in common, which contains a mitochondrial targeting signal that is essential for mitochondrial localization. Many alternative splice variants for this gene have been described, but the full-length nature for every variant has not been determined. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, M_CAP, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.038028896).
• BP6: Variant 3-9756791-G-A is Benign according to our data. Variant chr3-9756791-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2653500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9756791-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OGG1	NM_002542.6	c.923G>A	p.Gly308Glu	missense_variant	6/7	ENST00000344629.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OGG1	ENST00000344629.12	c.923G>A	p.Gly308Glu	missense_variant	6/7	1	NM_002542.6	P1

Frequencies

GnomAD3 genomes AF: 0.00359 AC: 546 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00569

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00387 AC: 972 AN: 251476 Hom.: 4 AF XY: 0.00394 AC XY: 536 AN XY: 135916

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00648

Gnomad OTH exome AF: 0.00521

GnomAD4 exome AF: 0.00501 AC: 7323 AN: 1461838 Hom.: 26 Cov.: 34 AF XY: 0.00503 AC XY: 3655 AN XY: 727218

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00400

Gnomad4 ASJ exome AF: 0.00295

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000568

Gnomad4 FIN exome AF: 0.00105

Gnomad4 NFE exome AF: 0.00599

Gnomad4 OTH exome AF: 0.00434

GnomAD4 genome AF: 0.00358 AC: 545 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.00318 AC XY: 237 AN XY: 74430

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00568

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00565 Hom.: 7

Bravo AF: 0.00392

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00412 AC: 500

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00660

EpiControl AF: 0.00610

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

OGG1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

OGG1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.038	T;T;T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Pathogenic	3.6	H;H;H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.3	D;D;D;D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0050	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;.
Vest4		0.95
MVP		0.92
MPC		0.58
ClinPred		0.086	T
GERP RS		5.4
Varity_R		0.98
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs113561019; hg19: chr3-9798475; COSMIC: COSV99042665; COSMIC: COSV99042665;