rs879254134

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000440232.7(POLD1):ā€‹c.3103G>Cā€‹(p.Glu1035Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000835 in 1,556,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1035D) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.000046 ( 0 hom., cov: 34)
Exomes š‘“: 0.0000043 ( 0 hom. )

Consequence

POLD1
ENST00000440232.7 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 3.28
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 -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.25310546).
BS2
High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLD1NM_002691.4 linkuse as main transcriptc.3103G>C p.Glu1035Gln missense_variant 25/27 ENST00000440232.7 NP_002682.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLD1ENST00000440232.7 linkuse as main transcriptc.3103G>C p.Glu1035Gln missense_variant 25/271 NM_002691.4 ENSP00000406046 P1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152150
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.000145
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000427
AC:
6
AN:
1403892
Hom.:
0
Cov.:
33
AF XY:
0.00000433
AC XY:
3
AN XY:
693080
show subpopulations
Gnomad4 AFR exome
AF:
0.000125
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:
0.00
Gnomad4 NFE exome
AF:
9.25e-7
Gnomad4 OTH exome
AF:
0.0000172
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152266
Hom.:
0
Cov.:
34
AF XY:
0.0000537
AC XY:
4
AN XY:
74434
show subpopulations
Gnomad4 AFR
AF:
0.000168
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoFeb 24, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 02, 2024Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19296856, 32041611) -
POLD1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesSep 12, 2023The POLD1 c.3103G>C variant is predicted to result in the amino acid substitution p.Glu1035Gln. This variant was reported in an individual with lipodystrophy (Table S4, Dron. 2020. PubMed ID: 32041611). This variant is reported in 0.0056% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-50920337-G-C), and is reported as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/246168/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalFeb 06, 2024- -
Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 18, 2024This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 1035 of the POLD1 protein (p.Glu1035Gln). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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: 246168). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLD1 protein function with a negative predictive value of 80%. 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
Benign
0.11
BayesDel_addAF
Benign
-0.098
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Benign
0.13
T;.;.;T
Eigen
Benign
-0.073
Eigen_PC
Benign
-0.040
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.94
.;.;D;D
M_CAP
Benign
0.052
D
MetaRNN
Benign
0.25
T;T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.5
L;.;.;L
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-0.99
N;.;.;.
REVEL
Benign
0.12
Sift
Benign
0.096
T;.;.;.
Sift4G
Benign
0.32
T;T;T;T
Polyphen
0.13
B;.;.;B
Vest4
0.40
MutPred
0.27
Loss of helix (P = 0.0167);.;.;Loss of helix (P = 0.0167);
MVP
0.68
MPC
0.84
ClinPred
0.71
D
GERP RS
3.0
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.8
Varity_R
0.46
gMVP
0.55

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: rs879254134; hg19: chr19-50920337; API