rs149096523

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_002691.4(POLD1):​c.714G>A​(p.Thr238Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000408 in 1,610,868 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00042 ( 1 hom. )

Consequence

POLD1
NM_002691.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.389
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 -15 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.35).
BP6
Variant 19-50402329-G-A is Benign according to our data. Variant chr19-50402329-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 220847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50402329-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.389 with no splicing effect.
BS2
High AC in GnomAd4 at 44 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLD1NM_002691.4 linkc.714G>A p.Thr238Thr synonymous_variant Exon 6 of 27 ENST00000440232.7 NP_002682.2 P28340A0A024R4F4Q59FA0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLD1ENST00000440232.7 linkc.714G>A p.Thr238Thr synonymous_variant Exon 6 of 27 1 NM_002691.4 ENSP00000406046.1 P28340

Frequencies

GnomAD3 genomes
AF:
0.000296
AC:
45
AN:
152260
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000719
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000411
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000207
AC:
51
AN:
246412
Hom.:
0
AF XY:
0.000187
AC XY:
25
AN XY:
133582
show subpopulations
Gnomad AFR exome
AF:
0.000127
Gnomad AMR exome
AF:
0.000379
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000553
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000298
Gnomad OTH exome
AF:
0.000332
GnomAD4 exome
AF:
0.000420
AC:
613
AN:
1458490
Hom.:
1
Cov.:
34
AF XY:
0.000389
AC XY:
282
AN XY:
725046
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.000472
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000502
Gnomad4 OTH exome
AF:
0.000465
GnomAD4 genome
AF:
0.000289
AC:
44
AN:
152378
Hom.:
0
Cov.:
33
AF XY:
0.000322
AC XY:
24
AN XY:
74516
show subpopulations
Gnomad4 AFR
AF:
0.0000721
Gnomad4 AMR
AF:
0.000718
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000397
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.000168
Hom.:
0
Bravo
AF:
0.000310
EpiCase
AF:
0.000763
EpiControl
AF:
0.000237

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:5
-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 20, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

POLD1: BP4, BP7 -

Sep 12, 2022
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:4
Feb 28, 2018
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 21, 2018
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 21, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Colorectal cancer, susceptibility to, 10 Benign:3
May 28, 2019
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2025
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:3
Jul 07, 2015
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This 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. -

Mar 24, 2021
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Dec 01, 2024
Molecular Diagnostics Laboratory, Catalan Institute of Oncology
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BA1, BP4, BP7 c.714G>A, located in exon 6 of the POLD1 gene, is predicted to result in no amino acid change, p.(Thr238=) (BP7). This variant is found in 56/264174 alleles at a frequency of 0.02% in the gnomAD v2.1.1 database, non-cancer dataset (BA1). The SpliceAI algorithm predicts no significant impact on splicing (BP4). To our knowledge, neither relevant clinical data nor well-established functional studies have been reported for this variant. This variant has been reported in the ClinVar database (9x benign, 3x likely benign) and in LOVD (2x likely benign). Based on currently available information, the variant c.714G>A should be considered a likely benign variant, according to ACMG/AMP classification guidelines. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.35
CADD
Benign
12
DANN
Benign
0.96
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.8

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: rs149096523; hg19: chr19-50905586; COSMIC: COSV101486829; COSMIC: COSV101486829; API