rs2230245

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002691.4(POLD1):​c.1485C>T​(p.Thr495Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,580,166 control chromosomes in the GnomAD database, including 11,895 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.099 ( 966 hom., cov: 32)
Exomes 𝑓: 0.12 ( 10929 hom. )

Consequence

POLD1
NM_002691.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -5.27
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 Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
Variant 19-50406508-C-T is Benign according to our data. Variant chr19-50406508-C-T is described in ClinVar as [Benign]. Clinvar id is 258787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50406508-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-5.27 with no splicing effect.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLD1NM_002691.4 linkuse as main transcriptc.1485C>T p.Thr495Thr synonymous_variant 12/27 ENST00000440232.7 NP_002682.2 P28340A0A024R4F4Q59FA0

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLD1ENST00000440232.7 linkuse as main transcriptc.1485C>T p.Thr495Thr synonymous_variant 12/271 NM_002691.4 ENSP00000406046.1 P28340

Frequencies

GnomAD3 genomes
AF:
0.0987
AC:
15005
AN:
152050
Hom.:
964
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0411
Gnomad AMI
AF:
0.193
Gnomad AMR
AF:
0.0853
Gnomad ASJ
AF:
0.173
Gnomad EAS
AF:
0.00847
Gnomad SAS
AF:
0.137
Gnomad FIN
AF:
0.170
Gnomad MID
AF:
0.117
Gnomad NFE
AF:
0.124
Gnomad OTH
AF:
0.117
GnomAD3 exomes
AF:
0.105
AC:
20740
AN:
198334
Hom.:
1366
AF XY:
0.109
AC XY:
11565
AN XY:
106122
show subpopulations
Gnomad AFR exome
AF:
0.0340
Gnomad AMR exome
AF:
0.0585
Gnomad ASJ exome
AF:
0.171
Gnomad EAS exome
AF:
0.0122
Gnomad SAS exome
AF:
0.141
Gnomad FIN exome
AF:
0.167
Gnomad NFE exome
AF:
0.115
Gnomad OTH exome
AF:
0.116
GnomAD4 exome
AF:
0.119
AC:
169994
AN:
1427996
Hom.:
10929
Cov.:
35
AF XY:
0.120
AC XY:
84765
AN XY:
707616
show subpopulations
Gnomad4 AFR exome
AF:
0.0393
Gnomad4 AMR exome
AF:
0.0620
Gnomad4 ASJ exome
AF:
0.173
Gnomad4 EAS exome
AF:
0.00795
Gnomad4 SAS exome
AF:
0.140
Gnomad4 FIN exome
AF:
0.162
Gnomad4 NFE exome
AF:
0.122
Gnomad4 OTH exome
AF:
0.123
GnomAD4 genome
AF:
0.0987
AC:
15013
AN:
152170
Hom.:
966
Cov.:
32
AF XY:
0.100
AC XY:
7449
AN XY:
74374
show subpopulations
Gnomad4 AFR
AF:
0.0411
Gnomad4 AMR
AF:
0.0852
Gnomad4 ASJ
AF:
0.173
Gnomad4 EAS
AF:
0.00829
Gnomad4 SAS
AF:
0.137
Gnomad4 FIN
AF:
0.170
Gnomad4 NFE
AF:
0.124
Gnomad4 OTH
AF:
0.118
Alfa
AF:
0.112
Hom.:
690
Bravo
AF:
0.0890
Asia WGS
AF:
0.0770
AC:
265
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, criteria provided, single submitterclinical testingGeneDxOct 29, 2015This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 25, 2016Variant summary: The c.1485C>T (p.Thr495=) in POLD1 gene is a synonymous change that involves a non-conserved nucleotide. 2/5 programs in Alamut predict that this variant may affect the normal splicing pattern by weakening the neighboring donor site, however no functional studies supporting these predictions were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.124 (5844/47134 chrs tested), including numerous homozygous occurrences. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000142). The variant of interest has not, to our knowledge, been reported in publications or cited by multiple reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Colorectal cancer, susceptibility to, 10 Benign:2
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Mandibular hypoplasia-deafness-progeroid syndrome Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabOct 25, 2021- -
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 20, 2015This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.52
CADD
Benign
2.9
DANN
Benign
0.61
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9

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: rs2230245; hg19: chr19-50909765; API