19-50415766-C-G
Variant summary
Our verdict is . The variant received 1 ACMG points: 2P and 1B. PM2BP4
Uncertain significance
The NM_002691.4(POLD1):c.2760C>G(p.Asp920Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000191 in 1,570,836 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 Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D920G) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 7.0e-7 ( 0 hom. )
Consequence
POLD1
NM_002691.4 missense
NM_002691.4 missense
Scores
5
8
6
Clinical Significance
Conservation
PhyloP100: 1.99
Publications
0 publications found
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]
POLD1 Gene-Disease associations (from GenCC):
- mandibular hypoplasia-deafness-progeroid syndromeInheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Ambry Genetics, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
- POLD1-related polyposis and colorectal cancer syndromeInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen
- colorectal cancer, susceptibility to, 10Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
- immunodeficiency 120Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, PanelApp Australia
- Polymerase proofreading-related adenomatous polyposisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- non-severe combined immunodeficiency due to polymerase delta deficiencyInheritance: AR Classification: LIMITED Submitted by: ClinGen
Genome browser will be placed here
new If you want to explore the variant's impact on the transcript NM_002691.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.
ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (REVEL=0.213).
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_002691.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| POLD1 | MANE Select | c.2760C>G | p.Asp920Glu | missense | Exon 22 of 27 | NP_002682.2 | P28340 | ||
| POLD1 | c.2838C>G | p.Asp946Glu | missense | Exon 21 of 26 | NP_001295561.1 | M0R2B7 | |||
| POLD1 | c.2760C>G | p.Asp920Glu | missense | Exon 22 of 27 | NP_001243778.1 | P28340 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| POLD1 | TSL:1 MANE Select | c.2760C>G | p.Asp920Glu | missense | Exon 22 of 27 | ENSP00000406046.1 | P28340 | ||
| POLD1 | TSL:1 | c.2838C>G | p.Asp946Glu | missense | Exon 22 of 27 | ENSP00000472445.1 | M0R2B7 | ||
| POLD1 | TSL:1 | c.2760C>G | p.Asp920Glu | missense | Exon 22 of 27 | ENSP00000473052.1 | P28340 |
Frequencies
GnomAD3 genomes 0.0000132 AC: 2AN: 151676Hom.: 0 Cov.: 31 show subpopulations
GnomAD3 genomes
AF:
AC:
2
AN:
151676
Hom.:
Cov.:
31
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:
GnomAD4 exome AF: 7.05e-7 AC: 1AN: 1419160Hom.: 0 Cov.: 33 AF XY: 0.00000142 AC XY: 1AN XY: 702504 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
1419160
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
702504
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
1
AN:
32906
American (AMR)
AF:
AC:
0
AN:
39254
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25178
East Asian (EAS)
AF:
AC:
0
AN:
38300
South Asian (SAS)
AF:
AC:
0
AN:
80896
European-Finnish (FIN)
AF:
AC:
0
AN:
46944
Middle Eastern (MID)
AF:
AC:
0
AN:
4084
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1092968
Other (OTH)
AF:
AC:
0
AN:
58630
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome 0.0000132 AC: 2AN: 151676Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74046 show subpopulations
GnomAD4 genome
AF:
AC:
2
AN:
151676
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
74046
show subpopulations
African (AFR)
AF:
AC:
2
AN:
41258
American (AMR)
AF:
AC:
0
AN:
15230
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3466
East Asian (EAS)
AF:
AC:
0
AN:
5112
South Asian (SAS)
AF:
AC:
0
AN:
4802
European-Finnish (FIN)
AF:
AC:
0
AN:
10584
Middle Eastern (MID)
AF:
AC:
0
AN:
310
European-Non Finnish (NFE)
AF:
AC:
0
AN:
67916
Other (OTH)
AF:
AC:
0
AN:
2086
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions
View on ClinVar Significance:Uncertain significance
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
-
1
-
Colorectal cancer, susceptibility to, 10 (1)
-
1
-
Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome (1)
-
1
-
Hereditary cancer-predisposing syndrome (1)
-
1
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
PhyloP100
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.
Publications
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Other links and lift over
dbSNP: rs1057521209 ;
hg19: chr19-50919023;