19-50414986-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_002691.4(POLD1):​c.2560G>T​(p.Asp854Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000317 in 1,575,790 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000034 ( 1 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

5
6
8

Clinical Significance

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

Conservation

PhyloP100: 6.00
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 -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.763
BS2
High AC in GnomAdExome4 at 49 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLD1NM_002691.4 linkc.2560G>T p.Asp854Tyr missense_variant Exon 20 of 27 ENST00000440232.7 NP_002682.2 P28340A0A024R4F4Q59FA0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLD1ENST00000440232.7 linkc.2560G>T p.Asp854Tyr missense_variant Exon 20 of 27 1 NM_002691.4 ENSP00000406046.1 P28340

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152172
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:
0.0000251
AC:
5
AN:
199096
Hom.:
0
AF XY:
0.0000462
AC XY:
5
AN XY:
108242
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:
0.00
Gnomad NFE exome
AF:
0.0000459
Gnomad OTH exome
AF:
0.000202
GnomAD4 exome
AF:
0.0000344
AC:
49
AN:
1423618
Hom.:
1
Cov.:
31
AF XY:
0.0000468
AC XY:
33
AN XY:
705588
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:
0.0000486
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000394
Gnomad4 OTH exome
AF:
0.0000341
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152172
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74342
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:
0.00000828
AC:
1

ClinVar

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

Submissions by phenotype

not provided Uncertain:2
Jun 23, 2019
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 28, 2017
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Colorectal cancer, susceptibility to, 10 Uncertain:1
Dec 23, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 854 of the POLD1 protein (p.Asp854Tyr). This variant is present in population databases (rs373650022, gnomAD 0.005%). 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: 239300). 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) 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
Feb 05, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.D854Y variant (also known as c.2560G>T), located in coding exon 19 of the POLD1 gene, results from a G to T substitution at nucleotide position 2560. The aspartic acid at codon 854 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.35
BayesDel_addAF
Benign
-0.026
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.35
T;.;.;T
Eigen
Benign
0.092
Eigen_PC
Benign
0.045
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Pathogenic
0.98
.;.;D;D
M_CAP
Pathogenic
0.29
D
MetaRNN
Pathogenic
0.76
D;D;D;D
MetaSVM
Benign
-0.97
T
MutationAssessor
Uncertain
2.8
M;.;.;M
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-6.0
D;.;.;.
REVEL
Uncertain
0.29
Sift
Uncertain
0.014
D;.;.;.
Sift4G
Benign
0.082
T;T;T;T
Polyphen
0.41
B;.;.;B
Vest4
0.68
MVP
0.51
MPC
1.0
ClinPred
0.96
D
GERP RS
3.4
Varity_R
0.60
gMVP
0.80

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: rs373650022; hg19: chr19-50918243; API