19-50407184-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002691.4(POLD1):​c.1686+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000716 in 1,592,908 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

POLD1
NM_002691.4 intron

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -3.19
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 Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.7).
BP6
Variant 19-50407184-C-T is Benign according to our data. Variant chr19-50407184-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLD1NM_002691.4 linkc.1686+10C>T intron_variant Intron 13 of 26 ENST00000440232.7 NP_002682.2 P28340A0A024R4F4Q59FA0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLD1ENST00000440232.7 linkc.1686+10C>T intron_variant Intron 13 of 26 1 NM_002691.4 ENSP00000406046.1 P28340

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152158
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000332
AC:
8
AN:
241148
Hom.:
0
AF XY:
0.0000306
AC XY:
4
AN XY:
130740
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000549
Gnomad SAS exome
AF:
0.0000338
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000555
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000715
AC:
103
AN:
1440750
Hom.:
0
Cov.:
33
AF XY:
0.0000673
AC XY:
48
AN XY:
713104
show subpopulations
Gnomad4 AFR exome
AF:
0.0000302
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000766
Gnomad4 SAS exome
AF:
0.0000352
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000830
Gnomad4 OTH exome
AF:
0.0000843
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152158
Hom.:
0
Cov.:
30
AF XY:
0.0000673
AC XY:
5
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000102
Hom.:
0
Bravo
AF:
0.0000756

ClinVar

Significance: Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
May 30, 2017
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jun 05, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: POLD1 c.1686+10C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.3e-05 in 241148 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1686+10C>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Sep 12, 2019
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Carcinoma of colon Benign:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

The POLD1 c.1686+10C>T variant was not identified in the literature. The variant was identified dbSNP (rs372652150) as “with likely benign allele” and ClinVar (classified as likely benign by Invitae and GeneDx). The variant was identified in control databases in 11 of 267,230 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 23,800 chromosomes (freq: 0.00008), European in 7 of 123,466 chromosomes (freq: 0.00006), East Asian in 1 of 18,704 chromosomes (freq: 0.00005), and South Asian in 1 of 29,814 chromosomes (freq: 0.00003). The variant was not observed in the Other, Latino, Ashkenazi Jewish, or Finnish, populations. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Colorectal cancer, susceptibility to, 10 Benign:1
Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.70
CADD
Benign
0.39
DANN
Benign
0.85
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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: rs372652150; hg19: chr19-50910441; COSMIC: COSV70954692; COSMIC: COSV70954692; API