rs3136797

Positions:

• chr8-42369287-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002690.3(POLB):​c.725C>G​(p.Pro242Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0152 in 1,581,432 control chromosomes in the GnomAD database, including 256 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.011 (12 hom., cov: 32)
  • Exomes 𝑓: 0.016 (244 hom.)
• Consequence: POLB NM_002690.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.48

Genes affected

POLB (HGNC:9174): (DNA polymerase beta) The protein encoded by this gene is a DNA polymerase involved in base excision and repair, also called gap-filling DNA synthesis. The encoded protein, acting as a monomer, is normally found in the cytoplasm, but it translocates to the nucleus upon DNA damage. Several transcript variants of this gene exist, but the full-length nature of only one has been described to date. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059150755).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0105 (1600/152136) while in subpopulation NFE AF= 0.0182 (1234/67988). AF 95% confidence interval is 0.0173. There are 12 homozygotes in gnomad4. There are 723 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLB	NM_002690.3	c.725C>G	p.Pro242Arg	missense_variant	12/14	ENST00000265421.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLB	ENST00000265421.9	c.725C>G	p.Pro242Arg	missense_variant	12/14	1	NM_002690.3	P1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1600 AN: 152018 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0106 AC: 2618 AN: 247430 Hom.: 21 AF XY: 0.0103 AC XY: 1378 AN XY: 133960

Gnomad AFR exome AF: 0.00208

Gnomad AMR exome AF: 0.00357

Gnomad ASJ exome AF: 0.00319

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00412

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0156 AC: 22359 AN: 1429296 Hom.: 244 Cov.: 24 AF XY: 0.0154 AC XY: 11011 AN XY: 713068

Gnomad4 AFR exome AF: 0.00233

Gnomad4 AMR exome AF: 0.00396

Gnomad4 ASJ exome AF: 0.00282

Gnomad4 EAS exome AF: 0.0000510

Gnomad4 SAS exome AF: 0.00392

Gnomad4 FIN exome AF: 0.0139

Gnomad4 NFE exome AF: 0.0187

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.0105 AC: 1600 AN: 152136 Hom.: 12 Cov.: 32 AF XY: 0.00972 AC XY: 723 AN XY: 74376

Gnomad4 AFR AF: 0.00275

Gnomad4 AMR AF: 0.00642

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.0182

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0159 Hom.: 18

Bravo AF: 0.00987

TwinsUK AF: 0.0197 AC: 73

ALSPAC AF: 0.0221 AC: 85

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0151 AC: 130

ExAC AF: 0.0111 AC: 1341

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0154

EpiControl AF: 0.0144

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.40	T;T
Eigen	Benign	0.087
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Benign	0.12
Sift	Benign	0.063	T;D
Sift4G	Benign	0.22	T;D
Polyphen		0.0	B;.
Vest4		0.18
MPC		0.68
ClinPred		0.039	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3136797; hg19: chr8-42226805;