rs1555789803

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_002691.4(POLD1):​c.449C>A​(p.Thr150Asn) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

POLD1
NM_002691.4 missense

Scores

2
5
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.647
Variant links:
Genes affected
POLD1 (HGNC:9175): (DNA polymerase delta 1, catalytic subunit) This gene encodes the 125-kDa catalytic 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. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Mar 2012]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.4036252).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLD1NM_002691.4 linkuse as main transcriptc.449C>A p.Thr150Asn missense_variant 4/27 ENST00000440232.7 NP_002682.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLD1ENST00000440232.7 linkuse as main transcriptc.449C>A p.Thr150Asn missense_variant 4/271 NM_002691.4 ENSP00000406046 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 11, 2023The p.T150N variant (also known as c.449C>A), located in coding exon 3 of the POLD1 gene, results from a C to A substitution at nucleotide position 449. The threonine at codon 150 is replaced by asparagine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.70
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
17
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.55
D;.;.;.;D
Eigen
Benign
-0.034
Eigen_PC
Benign
-0.023
FATHMM_MKL
Benign
0.73
D
LIST_S2
Uncertain
0.89
.;.;D;D;D
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.40
T;T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.90
L;.;.;.;L
MutationTaster
Benign
0.74
N
PrimateAI
Benign
0.45
T
PROVEAN
Uncertain
-3.1
D;.;.;.;.
REVEL
Benign
0.090
Sift
Uncertain
0.0010
D;.;.;.;.
Sift4G
Pathogenic
0.0010
D;D;D;D;D
Polyphen
0.40
B;.;.;.;B
Vest4
0.55
MutPred
0.57
Loss of glycosylation at T150 (P = 0.0723);Loss of glycosylation at T150 (P = 0.0723);Loss of glycosylation at T150 (P = 0.0723);Loss of glycosylation at T150 (P = 0.0723);Loss of glycosylation at T150 (P = 0.0723);
MVP
0.60
MPC
0.42
ClinPred
0.57
D
GERP RS
1.4
Varity_R
0.72
gMVP
0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-50905167; API