Variant 11-74625409-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006591.3(POLD3):c.735T>G(p.Asn245Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Consequence

POLD3
NM_006591.3 missense, splice_region

Scores

Splicing: ADA: 0.05921

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.82

Variant links:

Genes affected

POLD3 (HGNC:20932): (DNA polymerase delta 3, accessory subunit) This gene encodes the 66-kDa subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3' to 5' exonuclease activity and plays a critical role in DNA replication and repair. The encoded protein plays a role in regulating the activity of DNA polymerase delta through interactions with other subunits and the processivity cofactor proliferating cell nuclear antigen (PCNA). Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Mar 2012]

POLD3 links:

POLD3 (HGNC:):

POLD3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23633587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD3	NM_006591.3 linkuse as main transcript	c.735T>G	p.Asn245Lys	missense_variant, splice_region_variant	8/12	ENST00000263681.7	NP_006582.1	Q15054-1A0A024R5M8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
POLD3	ENST00000263681.7 linkuse as main transcript	c.735T>G	p.Asn245Lys	missense_variant, splice_region_variant	8/12	1	NM_006591.3	ENSP00000263681.2	Q15054-1
POLD3	ENST00000527458.5 linkuse as main transcript	c.618T>G	p.Asn206Lys	missense_variant, splice_region_variant	8/12	1		ENSP00000432951.1	Q15054-2
POLD3	ENST00000532497.5 linkuse as main transcript	c.417T>G	p.Asn139Lys	missense_variant, splice_region_variant	7/11	1		ENSP00000436018.1	Q15054-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2024

The c.735T>G (p.N245K) alteration is located in exon 8 (coding exon 8) of the POLD3 gene. This alteration results from a T to G substitution at nucleotide position 735, causing the asparagine (N) at amino acid position 245 to be replaced by a lysine (K). 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

0.15

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.055

T;.;.

Eigen

Benign

0.021

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.72

T;T;T

M_CAP

Benign

0.0030

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.4

M;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.15

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.33

T;T;T

Sift4G

Benign

0.45

T;T;T

Polyphen

0.38

B;.;.

Vest4

0.27

MutPred

0.43

Loss of ubiquitination at K248 (P = 0.026);.;.;

MVP

0.61

MPC

0.16

ClinPred

0.35

GERP RS

5.7

Varity_R

0.076

gMVP

0.069

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.059

dbscSNV1_RF

Benign

0.15

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over