chr19-50414875-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002691.4(POLD1):​c.2449C>T​(p.Arg817Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000498 in 1,607,146 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

3
6
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.218
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 -4 ACMG points.

BS2
High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLD1NM_002691.4 linkuse as main transcriptc.2449C>T p.Arg817Trp missense_variant 20/27 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.2449C>T p.Arg817Trp missense_variant 20/271 NM_002691.4 ENSP00000406046.1 P28340

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152238
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000162
AC:
4
AN:
247376
Hom.:
0
AF XY:
0.0000224
AC XY:
3
AN XY:
133784
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000111
Gnomad SAS exome
AF:
0.0000332
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000893
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000481
AC:
7
AN:
1454908
Hom.:
0
Cov.:
31
AF XY:
0.00000830
AC XY:
6
AN XY:
723318
show subpopulations
Gnomad4 AFR exome
AF:
0.0000601
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000254
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000361
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152238
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74384
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:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 14, 2022Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20951805) -
Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 03, 2024This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 817 of the POLD1 protein (p.Arg817Trp). This variant is present in population databases (rs148176230, gnomAD 0.01%). 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: 566682). 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 24, 2024The p.R817W variant (also known as c.2449C>T), located in coding exon 19 of the POLD1 gene, results from a C to T substitution at nucleotide position 2449. The arginine at codon 817 is replaced by tryptophan, an amino acid with dissimilar 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
Benign
0.16
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.39
T;.;.;T
Eigen
Benign
0.13
Eigen_PC
Benign
-0.14
FATHMM_MKL
Benign
0.33
N
LIST_S2
Uncertain
0.94
.;.;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Uncertain
0.56
D;D;D;D
MetaSVM
Benign
-0.78
T
MutationAssessor
Pathogenic
3.2
M;.;.;M
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-4.1
D;.;.;.
REVEL
Benign
0.14
Sift
Pathogenic
0.0
D;.;.;.
Sift4G
Pathogenic
0.0010
D;D;D;D
Polyphen
0.99
D;.;.;D
Vest4
0.34
MVP
0.62
MPC
1.5
ClinPred
0.96
D
GERP RS
-0.57
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.43
gMVP
0.47

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs148176230; hg19: chr19-50918132; API