chr9-113408974-C-G

Variant names:

• chr9-113408974-C-G
• rs779452088
• NM_017443.5:c.281G>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.281G>C​(p.Arg94Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R94L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLE3 NM_017443.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21136284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE3	NM_017443.5	c.281G>C	p.Arg94Pro	missense_variant	Exon 5 of 5	ENST00000374171.5	NP_059139.3
POLE3	NM_001278255.1	c.281G>C	p.Arg94Pro	missense_variant	Exon 5 of 5		NP_001265184.1
POLE3	NM_001433719.1	c.281G>C	p.Arg94Pro	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.281G>C	p.Arg94Pro	missense_variant	Exon 5 of 5	2	NM_017443.5	ENSP00000363286.4
POLE3	ENST00000374169.7	c.281G>C	p.Arg94Pro	missense_variant	Exon 4 of 4	1		ENSP00000363284.3
POLE3	ENST00000475080.1	n.425G>C		non_coding_transcript_exon_variant	Exon 3 of 3	2
POLE3	ENST00000479871.1	n.657G>C		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1461550 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727098

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111862

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Benign	0.33	T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.77	.;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L
PhyloP100		1.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.15
Sift	Benign	0.033	D;D
Sift4G	Uncertain	0.032	D;D
Polyphen		0.90	P;P
Vest4		0.40
MutPred		0.30		Loss of MoRF binding (P = 0.0031);Loss of MoRF binding (P = 0.0031);
MVP		0.38
MPC		0.66
ClinPred		0.64	D
GERP RS		4.1
Varity_R		0.69
gMVP		0.55
Mutation Taster		=86/14	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: rs779452088; hg19: chr9-116171254;