rs763850764
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PM4_SupportingBS2
The NM_002691.4(POLD1):c.2446_2448del(p.Ser816del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000449 in 1,605,136 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F814F) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000047 ( 2 hom. )
Consequence
POLD1
NM_002691.4 inframe_deletion
NM_002691.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.65
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 -3 ACMG points.
PM4
?
Nonframeshift variant in NON repetitive region in NM_002691.4. Strenght limited to Supporting due to length of the change: 1aa.
BS2
?
High AC in GnomAdExome4 at 69 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.2446_2448del | p.Ser816del | inframe_deletion | 20/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.2446_2448del | p.Ser816del | inframe_deletion | 20/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152142Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
3
AN:
152142
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000893 AC: 22AN: 246470Hom.: 1 AF XY: 0.000128 AC XY: 17AN XY: 133322
GnomAD3 exomes
AF:
AC:
22
AN:
246470
Hom.:
AF XY:
AC XY:
17
AN XY:
133322
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000475 AC: 69AN: 1452994Hom.: 2 AF XY: 0.0000706 AC XY: 51AN XY: 722312
GnomAD4 exome
AF:
AC:
69
AN:
1452994
Hom.:
AF XY:
AC XY:
51
AN XY:
722312
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152142Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74334
GnomAD4 genome
?
AF:
AC:
3
AN:
152142
Hom.:
Cov.:
33
AF XY:
AC XY:
3
AN XY:
74334
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Colorectal cancer, susceptibility to, 10 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 08, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 29, 2022 | This variant, c.2446_2448del, results in the deletion of 1 amino acid(s) of the POLD1 protein (p.Ser816del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs763850764, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 407984). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 27, 2023 | In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29056344, 20951805) - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 07, 2024 | This alteration is classified as 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:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at