19-50406314-A-G

Variant summary

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

The NM_002691.4(POLD1):ā€‹c.1375A>Gā€‹(p.Met459Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.000014 ( 0 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.90
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 20 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLD1NM_002691.4 linkc.1375A>G p.Met459Val missense_variant 11/27 ENST00000440232.7 NP_002682.2 P28340A0A024R4F4Q59FA0

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLD1ENST00000440232.7 linkc.1375A>G p.Met459Val missense_variant 11/271 NM_002691.4 ENSP00000406046.1 P28340

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251126
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135762
show subpopulations
Gnomad AFR exome
AF:
0.0000616
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1461700
Hom.:
0
Cov.:
36
AF XY:
0.0000151
AC XY:
11
AN XY:
727150
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 12, 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 469194). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 459 of the POLD1 protein (p.Met459Val). -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 08, 2023The p.M459V variant (also known as c.1375A>G), located in coding exon 10 of the POLD1 gene, results from an A to G substitution at nucleotide position 1375. The methionine at codon 459 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. 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
0.12
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
22
DANN
Benign
0.97
DEOGEN2
Benign
0.18
T;.;.;T
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.11
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Pathogenic
0.98
.;.;D;D
M_CAP
Benign
0.012
T
MetaRNN
Uncertain
0.45
T;T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.12
N;.;.;N
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-1.2
N;.;.;.
REVEL
Benign
0.079
Sift
Benign
0.18
T;.;.;.
Sift4G
Benign
0.29
T;T;T;T
Polyphen
0.0030
B;.;.;B
Vest4
0.58
MutPred
0.68
Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP
0.37
MPC
0.64
ClinPred
0.18
T
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.31
gMVP
0.53

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: rs774331018; hg19: chr19-50909571; API