11-74629258-C-T

Position:

• chr11-74629258-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006591.3(POLD3):​c.941C>T​(p.Thr314Ile) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLD3 NM_006591.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

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 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=0.20269305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD3	NM_006591.3	c.941C>T	p.Thr314Ile	missense_variant	9/12	ENST00000263681.7	NP_006582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD3	ENST00000263681.7	c.941C>T	p.Thr314Ile	missense_variant	9/12	1	NM_006591.3	ENSP00000263681.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

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

Apr 20, 2024

The c.941C>T (p.T314I) alteration is located in exon 9 (coding exon 9) of the POLD3 gene. This alteration results from a C to T substitution at nucleotide position 941, causing the threonine (T) at amino acid position 314 to be replaced by an isoleucine (I). 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	0.10
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.3	M;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.060
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.22
MutPred		0.36		Loss of phosphorylation at T314 (P = 0.011);.;.;
MVP		0.46
MPC		0.16
ClinPred		0.88	D
GERP RS		3.8
Varity_R		0.054
gMVP		0.048

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-74340303;