9-113410107-G-C

Variant names:

• chr9-113410107-G-C
• rs374274388
• NM_017443.5:c.100C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017443.5(POLE3):​c.100C>G​(p.Arg34Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,437,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R34W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: POLE3 NM_017443.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.69
• 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]

C9orf43 (HGNC:23570): (chromosome 9 open reading frame 43)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE3	NM_017443.5	c.100C>G	p.Arg34Gly	missense_variant	Exon 3 of 5	ENST00000374171.5	NP_059139.3
POLE3	NM_001278255.1	c.100C>G	p.Arg34Gly	missense_variant	Exon 3 of 5		NP_001265184.1
POLE3	NM_001433719.1	c.100C>G	p.Arg34Gly	missense_variant	Exon 2 of 4		NP_001420648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE3	ENST00000374171.5	c.100C>G	p.Arg34Gly	missense_variant	Exon 3 of 5	2	NM_017443.5	ENSP00000363286.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437704 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 712978

African (AFR) AF: 0.00 AC: 0 AN: 33208

American (AMR) AF: 0.00 AC: 0 AN: 40654

Ashkenazi Jewish (ASJ) AF: 0.0000391 AC: 1 AN: 25592

East Asian (EAS) AF: 0.00 AC: 0 AN: 38850

South Asian (SAS) AF: 0.00 AC: 0 AN: 82962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4882

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100908

Other (OTH) AF: 0.00 AC: 0 AN: 59416

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.2	M;M
PhyloP100		3.7
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.62		Loss of MoRF binding (P = 0.0336);Loss of MoRF binding (P = 0.0336);
MVP		0.66
MPC		1.0
ClinPred		1.0	D
GERP RS		4.9
PromoterAI		-0.036	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.9
Varity_R		0.79
gMVP		0.82
Mutation Taster		=89/11	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: rs374274388; hg19: chr9-116172387;