rs104893751

chr3-9750423-G-Achr3-9750423-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_002542.6(OGG1):c.137G>A(p.Arg46Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00333 in 1,613,860 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (8 hom.)
• Consequence: OGG1 NM_002542.6 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:3
• Conservation: PhyloP100: 6.30

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 Uncertain_significance. Variant got 1 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Dann, dbscSNV1_ADA, dbscSNV1_RF, Eigen, MutationAssessor [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OGG1	NM_002542.6	c.137G>A	p.Arg46Gln	missense_variant, splice_region_variant	1/7	ENST00000344629.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OGG1	ENST00000344629.12	c.137G>A	p.Arg46Gln	missense_variant, splice_region_variant	1/7	1	NM_002542.6	P1

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 343 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00367

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00221 AC: 553 AN: 249786 Hom.: 0 AF XY: 0.00223 AC XY: 301 AN XY: 135194

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.000561

Gnomad NFE exome AF: 0.00383

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00344 AC: 5035 AN: 1461558 Hom.: 8 Cov.: 31 AF XY: 0.00332 AC XY: 2412 AN XY: 727114

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00221

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.000584

Gnomad4 NFE exome AF: 0.00418

Gnomad4 OTH exome AF: 0.00288

GnomAD4 genome AF: 0.00225 AC: 343 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.00201 AC XY: 150 AN XY: 74468

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00368

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00309 Hom.: 1

Bravo AF: 0.00254

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00205 AC: 249

EpiCase AF: 0.00398

EpiControl AF: 0.00332

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jul 31, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Clear cell carcinoma of kidney Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	35
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.035	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.9	H;H;H;H;H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;D;.;.;.
Vest4		0.76
MVP		0.84
MPC		0.55
ClinPred		0.11	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.95
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.39		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs104893751; hg19: chr3-9792107; COSMIC: COSV100115398; COSMIC: COSV100115398;