9-113409612-T-G

Variant names:

• chr9-113409612-T-G
• NM_017443.5:c.269A>C

Variant summary

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

The NM_017443.5(POLE3):​c.269A>C​(p.Glu90Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLE3 NM_017443.5 missense, splice_region
• Scores: Splicing: ADA: 0.0002454
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.29
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE3	NM_017443.5	c.269A>C	p.Glu90Ala	missense_variant, splice_region_variant	Exon 4 of 5	ENST00000374171.5	NP_059139.3
POLE3	NM_001278255.1	c.269A>C	p.Glu90Ala	missense_variant, splice_region_variant	Exon 4 of 5		NP_001265184.1
POLE3	NM_001433719.1	c.269A>C	p.Glu90Ala	missense_variant, splice_region_variant	Exon 3 of 4		NP_001420648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE3	ENST00000374171.5	c.269A>C	p.Glu90Ala	missense_variant, splice_region_variant	Exon 4 of 5	2	NM_017443.5	ENSP00000363286.4
POLE3	ENST00000374169.7	c.269A>C	p.Glu90Ala	missense_variant, splice_region_variant	Exon 3 of 4	1		ENSP00000363284.3
POLE3	ENST00000475080.1	n.413A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	2
POLE3	ENST00000479871.1	n.645A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.269A>C (p.E90A) alteration is located in exon 4 (coding exon 3) of the POLE3 gene. This alteration results from a A to C substitution at nucleotide position 269, causing the glutamic acid (E) at amino acid position 90 to be replaced by an alanine (A). 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	0.21
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;D
Eigen	Benign	0.15
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	2.9	M;M
PhyloP100		7.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.025	D;D
Sift4G	Benign	0.087	T;T
Polyphen		1.0	D;D
Vest4		0.63
MutPred		0.29		Gain of MoRF binding (P = 0.0538);Gain of MoRF binding (P = 0.0538);
MVP		0.36
MPC		0.94
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.35
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.070
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

hg19: chr9-116171892; COSMIC: COSV99928470; COSMIC: COSV99928470;