rs754416243

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_002691.4(POLD1):​c.2888C>T​(p.Ala963Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000787 in 1,397,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000079 ( 0 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

1
8
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.83
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 -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.31151813).
BS2
High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLD1NM_002691.4 linkuse as main transcriptc.2888C>T p.Ala963Val missense_variant 23/27 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.2888C>T p.Ala963Val missense_variant 23/271 NM_002691.4 ENSP00000406046.1 P28340
ENSG00000142539ENST00000599632.1 linkuse as main transcriptc.95C>T p.Ala32Val missense_variant 2/105 ENSP00000473233.1 M0R3H8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000386
AC:
6
AN:
155544
Hom.:
0
AF XY:
0.0000726
AC XY:
6
AN XY:
82596
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:
0.000262
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000787
AC:
11
AN:
1397960
Hom.:
0
Cov.:
31
AF XY:
0.0000159
AC XY:
11
AN XY:
689730
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:
0.000139
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000188
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 14, 2022In 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. 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. ClinVar contains an entry for this variant (Variation ID: 537053). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. This variant is present in population databases (rs754416243, gnomAD 0.03%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 963 of the POLD1 protein (p.Ala963Val). -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsOct 17, 2024This alteration is classified as likely 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
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.50
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.28
T;.;.;T
Eigen
Benign
0.036
Eigen_PC
Benign
0.073
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Pathogenic
0.99
.;.;D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.31
T;T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.8
L;.;.;L
PrimateAI
Uncertain
0.68
T
PROVEAN
Uncertain
-3.0
D;.;.;.
REVEL
Benign
0.057
Sift
Uncertain
0.0040
D;.;.;.
Sift4G
Uncertain
0.010
D;D;D;D
Polyphen
0.22
B;.;.;B
Vest4
0.41
MutPred
0.50
Gain of methylation at K964 (P = 0.0416);.;.;Gain of methylation at K964 (P = 0.0416);
MVP
0.53
MPC
1.1
ClinPred
0.43
T
GERP RS
3.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.48
gMVP
0.34

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: rs754416243; hg19: chr19-50919720; COSMIC: COSV54531851; COSMIC: COSV54531851; API