19-50402247-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_002691.4(POLD1):​c.632G>C​(p.Arg211Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 1,597,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R211H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

4
12
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.48
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.869
BS2
High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLD1NM_002691.4 linkc.632G>C p.Arg211Pro missense_variant Exon 6 of 27 ENST00000440232.7 NP_002682.2 P28340A0A024R4F4Q59FA0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLD1ENST00000440232.7 linkc.632G>C p.Arg211Pro missense_variant Exon 6 of 27 1 NM_002691.4 ENSP00000406046.1 P28340

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152218
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000423
AC:
10
AN:
236504
Hom.:
0
AF XY:
0.0000156
AC XY:
2
AN XY:
127804
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000482
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000166
AC:
24
AN:
1444840
Hom.:
0
Cov.:
34
AF XY:
0.0000181
AC XY:
13
AN XY:
717002
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000417
Gnomad4 NFE exome
AF:
0.00000181
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152218
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jul 08, 2022
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Colorectal cancer, susceptibility to, 10 Uncertain:1
Nov 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 211 of the POLD1 protein (p.Arg211Pro). This variant is present in population databases (rs373192520, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 953892). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLD1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.61
D;.;.;D
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.99
.;.;D;D
M_CAP
Benign
0.042
D
MetaRNN
Pathogenic
0.87
D;D;D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.1
M;.;.;M
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-3.9
D;.;.;.
REVEL
Uncertain
0.30
Sift
Uncertain
0.0010
D;.;.;.
Sift4G
Pathogenic
0.0010
D;D;D;D
Polyphen
0.96
D;.;.;D
Vest4
0.85
MutPred
0.74
Loss of MoRF binding (P = 0.0088);Loss of MoRF binding (P = 0.0088);Loss of MoRF binding (P = 0.0088);Loss of MoRF binding (P = 0.0088);
MVP
0.80
MPC
0.87
ClinPred
0.84
D
GERP RS
4.2
Varity_R
0.96
gMVP
0.98

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

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

Other links and lift over

dbSNP: rs373192520; hg19: chr19-50905504; API