rs1555791139

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002691.4(POLD1):​c.1357G>A​(p.Gly453Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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

POLD1
NM_002691.4 missense

Scores

13
5
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.15
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLD1NM_002691.4 linkc.1357G>A p.Gly453Ser missense_variant 11/27 ENST00000440232.7 NP_002682.2 P28340A0A024R4F4Q59FA0

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLD1ENST00000440232.7 linkc.1357G>A p.Gly453Ser missense_variant 11/271 NM_002691.4 ENSP00000406046.1 P28340

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
35
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.69
D;.;.;D
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.90
.;.;D;D
M_CAP
Pathogenic
0.32
D
MetaRNN
Pathogenic
0.98
D;D;D;D
MetaSVM
Uncertain
0.31
D
MutationAssessor
Pathogenic
3.7
H;.;.;H
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-5.8
D;.;.;.
REVEL
Pathogenic
0.78
Sift
Pathogenic
0.0
D;.;.;.
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;.;.;D
Vest4
0.92
MutPred
0.91
Gain of phosphorylation at G453 (P = 0.0463);Gain of phosphorylation at G453 (P = 0.0463);Gain of phosphorylation at G453 (P = 0.0463);Gain of phosphorylation at G453 (P = 0.0463);
MVP
0.89
MPC
1.6
ClinPred
1.0
D
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.79
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.79
Position offset: -4

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: chr19-50909553; API