19-50416622-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002691.4(POLD1):​c.2966C>G​(p.Thr989Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,411,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T989A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

10
4
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.15

Publications

0 publications found
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]
POLD1 Gene-Disease associations (from GenCC):
  • POLD1-related polyposis and colorectal cancer syndrome
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • colorectal cancer, susceptibility to, 10
    Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
  • mandibular hypoplasia-deafness-progeroid syndrome
    Inheritance: AD, AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
  • Polymerase proofreading-related adenomatous polyposis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • immunodeficiency 120
    Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
  • non-severe combined immunodeficiency due to polymerase delta deficiency
    Inheritance: AR Classification: LIMITED Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLD1NM_002691.4 linkc.2966C>G p.Thr989Arg missense_variant Exon 24 of 27 ENST00000440232.7 NP_002682.2 P28340A0A024R4F4Q59FA0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLD1ENST00000440232.7 linkc.2966C>G p.Thr989Arg missense_variant Exon 24 of 27 1 NM_002691.4 ENSP00000406046.1 P28340
ENSG00000142539ENST00000599632.1 linkc.173C>G p.Thr58Arg missense_variant Exon 3 of 10 5 ENSP00000473233.1 M0R3H8

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
7.09e-7
AC:
1
AN:
1411024
Hom.:
0
Cov.:
34
AF XY:
0.00000143
AC XY:
1
AN XY:
698400
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
32248
American (AMR)
AF:
0.00
AC:
0
AN:
37962
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25282
East Asian (EAS)
AF:
0.00
AC:
0
AN:
36896
South Asian (SAS)
AF:
0.00
AC:
0
AN:
80668
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
43900
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5268
European-Non Finnish (NFE)
AF:
9.17e-7
AC:
1
AN:
1090202
Other (OTH)
AF:
0.00
AC:
0
AN:
58598
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
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
Cov.:
34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.86
BayesDel_addAF
Uncertain
0.037
T
BayesDel_noAF
Benign
-0.19
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.81
D;.;.;D
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Benign
0.42
N
LIST_S2
Pathogenic
0.99
.;.;D;D
M_CAP
Pathogenic
0.72
D
MetaRNN
Pathogenic
0.87
D;D;D;D
MetaSVM
Benign
-0.73
T
MutationAssessor
Pathogenic
4.3
H;.;.;H
PhyloP100
2.1
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-5.9
D;.;.;.
REVEL
Benign
0.27
Sift
Pathogenic
0.0
D;.;.;.
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;.;.;D
Vest4
0.62
MutPred
0.61
Gain of MoRF binding (P = 0.0073);.;.;Gain of MoRF binding (P = 0.0073);
MVP
0.83
MPC
1.7
ClinPred
1.0
D
GERP RS
2.7
Varity_R
0.86
gMVP
0.70
Mutation Taster
=19/81
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.19
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs866317622; hg19: chr19-50919879; API