19-50409223-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_002691.4(POLD1):​c.1994G>A​(p.Ser665Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,456,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S665G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

4
15

Clinical Significance

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

Conservation

PhyloP100: 3.83
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 -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.21323252).
BP6
Variant 19-50409223-G-A is Benign according to our data. Variant chr19-50409223-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 469232.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
POLD1NM_002691.4 linkuse as main transcriptc.1994G>A p.Ser665Asn missense_variant 16/27 ENST00000440232.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
POLD1ENST00000440232.7 linkuse as main transcriptc.1994G>A p.Ser665Asn missense_variant 16/271 NM_002691.4 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250462
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135506
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:
0.00000884
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1456354
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
724958
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:
0.00000271
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

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 testingInvitaeAug 17, 2023ClinVar contains an entry for this variant (Variation ID: 469232). 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. 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. 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 serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 665 of the POLD1 protein (p.Ser665Asn). -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 28, 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
Benign
0.16
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.21
T;.;.;T
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.15
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.96
.;.;D;D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.21
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.4
L;.;.;L
MutationTaster
Benign
0.92
D
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-2.1
N;.;.;.
REVEL
Benign
0.031
Sift
Benign
0.13
T;.;.;.
Sift4G
Benign
0.21
T;T;T;T
Polyphen
0.0020
B;.;.;B
Vest4
0.42
MutPred
0.42
Loss of phosphorylation at S665 (P = 0.0953);.;.;Loss of phosphorylation at S665 (P = 0.0953);
MVP
0.53
MPC
0.63
ClinPred
0.39
T
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.099
gMVP
0.50

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: rs757053149; hg19: chr19-50912480; API