11-74625513-G-C

Position:

• chr11-74625513-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006591.3(POLD3):​c.839G>C​(p.Gly280Ala) 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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLD3 NM_006591.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.324

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04469028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD3	NM_006591.3	c.839G>C	p.Gly280Ala	missense_variant	8/12	ENST00000263681.7	NP_006582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD3	ENST00000263681.7	c.839G>C	p.Gly280Ala	missense_variant	8/12	1	NM_006591.3	ENSP00000263681.2
POLD3	ENST00000527458.5	c.722G>C	p.Gly241Ala	missense_variant	8/12	1		ENSP00000432951.1
POLD3	ENST00000532497.5	c.521G>C	p.Gly174Ala	missense_variant	7/11	1		ENSP00000436018.1
POLD3	ENST00000524752.1	c.8G>C	p.Gly3Ala	missense_variant	1/5	2		ENSP00000432969.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2024

The c.839G>C (p.G280A) alteration is located in exon 8 (coding exon 8) of the POLD3 gene. This alteration results from a G to C substitution at nucleotide position 839, causing the glycine (G) at amino acid position 280 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	0.063
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.5
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T;.;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.045	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.71	N;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.5	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.79	T;T;T
Sift4G	Benign	0.74	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.095
MutPred		0.27		Loss of loop (P = 0.0073);.;.;
MVP		0.30
MPC		0.15
ClinPred		0.063	T
GERP RS		0.66
Varity_R		0.021
gMVP		0.038

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

Publications

LitVar

Other links and lift over

dbSNP: rs1591309577; hg19: chr11-74336558;