9-113408843-C-G

Variant names:

• chr9-113408843-C-G
• rs140173089
• NM_017443.5:c.412G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017443.5(POLE3):​c.412G>C​(p.Glu138Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000353 in 1,613,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: POLE3 NM_017443.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.48
• Publications: 2 publications found

Genes affected

POLE3 (HGNC:13546): (DNA polymerase epsilon 3, accessory subunit) POLE3 is a histone-fold protein that interacts with other histone-fold proteins to bind DNA in a sequence-independent manner. These histone-fold protein dimers combine within larger enzymatic complexes for DNA transcription, replication, and packaging.[supplied by OMIM, Apr 2004]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10254061).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE3	NM_017443.5	c.412G>C	p.Glu138Gln	missense_variant	Exon 5 of 5	ENST00000374171.5	NP_059139.3
POLE3	NM_001278255.1	c.412G>C	p.Glu138Gln	missense_variant	Exon 5 of 5		NP_001265184.1
POLE3	NM_001433719.1	c.412G>C	p.Glu138Gln	missense_variant	Exon 4 of 4		NP_001420648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE3	ENST00000374171.5	c.412G>C	p.Glu138Gln	missense_variant	Exon 5 of 5	2	NM_017443.5	ENSP00000363286.4
POLE3	ENST00000374169.7	c.412G>C	p.Glu138Gln	missense_variant	Exon 4 of 4	1		ENSP00000363284.3
POLE3	ENST00000479871.1	n.788G>C		non_coding_transcript_exon_variant	Exon 3 of 3	2
POLE3	ENST00000475080.1	n.*101G>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 250528 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1461102 Hom.: 0 Cov.: 30 AF XY: 0.0000303 AC XY: 22 AN XY: 726874

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1111470

Other (OTH) AF: 0.0000331 AC: 2 AN: 60352

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000755 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.000238

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.412G>C (p.E138Q) alteration is located in exon 5 (coding exon 4) of the POLE3 gene. This alteration results from a G to C substitution at nucleotide position 412, causing the glutamic acid (E) at amino acid position 138 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-0.081
Eigen_PC	Benign	0.094
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	.;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N
PhyloP100		4.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.78	N;N
REVEL	Benign	0.035
Sift	Benign	0.067	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.0080	B;B
Vest4		0.10
MVP		0.33
MPC		0.26
ClinPred		0.14	T
GERP RS		4.7
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.3
Varity_R		0.20
gMVP		0.11
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs140173089; hg19: chr9-116171123;