chr19-50402468-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_002691.4(POLD1):​c.773C>T​(p.Thr258Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000394 in 1,612,440 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T258R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

4
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:12

Conservation

PhyloP100: 0.737

Publications

8 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: Likely_benign. The variant received -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.011580497).
BP6
Variant 19-50402468-C-T is Benign according to our data. Variant chr19-50402468-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221166.We mark this variant Benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLD1NM_002691.4 linkc.773C>T p.Thr258Met missense_variant Exon 7 of 27 ENST00000440232.7 NP_002682.2 P28340A0A024R4F4Q59FA0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLD1ENST00000440232.7 linkc.773C>T p.Thr258Met missense_variant Exon 7 of 27 1 NM_002691.4 ENSP00000406046.1 P28340

Frequencies

GnomAD3 genomes
AF:
0.00175
AC:
267
AN:
152230
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00560
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00177
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00239
GnomAD2 exomes
AF:
0.000509
AC:
125
AN:
245402
AF XY:
0.000398
show subpopulations
Gnomad AFR exome
AF:
0.00556
Gnomad AMR exome
AF:
0.000646
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000901
Gnomad OTH exome
AF:
0.000334
GnomAD4 exome
AF:
0.000253
AC:
369
AN:
1460092
Hom.:
0
Cov.:
34
AF XY:
0.000238
AC XY:
173
AN XY:
726238
show subpopulations
African (AFR)
AF:
0.00709
AC:
237
AN:
33432
American (AMR)
AF:
0.000562
AC:
25
AN:
44446
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26058
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39632
South Asian (SAS)
AF:
0.0000698
AC:
6
AN:
85908
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53198
Middle Eastern (MID)
AF:
0.00295
AC:
17
AN:
5766
European-Non Finnish (NFE)
AF:
0.0000414
AC:
46
AN:
1111344
Other (OTH)
AF:
0.000630
AC:
38
AN:
60308
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.482
Heterozygous variant carriers
0
24
49
73
98
122
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<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
AF:
0.00175
AC:
266
AN:
152348
Hom.:
1
Cov.:
33
AF XY:
0.00180
AC XY:
134
AN XY:
74504
show subpopulations
African (AFR)
AF:
0.00556
AC:
231
AN:
41580
American (AMR)
AF:
0.00176
AC:
27
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10630
Middle Eastern (MID)
AF:
0.00340
AC:
1
AN:
294
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68020
Other (OTH)
AF:
0.00237
AC:
5
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.497
Heterozygous variant carriers
0
14
28
41
55
69
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000431
Hom.:
0
Bravo
AF:
0.00198
ESP6500AA
AF:
0.00522
AC:
23
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000536
AC:
65
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:12
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:4
Oct 06, 2020
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Apr 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

POLD1: BS1, BS2 -

Aug 30, 2019
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Uncertain:1Benign:2
Apr 24, 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:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 29, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely 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:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2
Nov 25, 2020
Sema4, Sema4
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:curation

- -

Aug 20, 2024
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome;C5935622:Immunodeficiency 120 Uncertain:1
Feb 21, 2024
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

POLD1-related disorder Benign:1
Mar 15, 2019
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.073
BayesDel_addAF
Benign
-0.62
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
20
DANN
Uncertain
0.98
DEOGEN2
Benign
0.40
T;.;.;T
Eigen
Benign
-0.59
Eigen_PC
Benign
-0.59
FATHMM_MKL
Benign
0.15
N
LIST_S2
Uncertain
0.93
.;.;D;D
MetaRNN
Benign
0.012
T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Uncertain
2.1
M;.;.;M
PhyloP100
0.74
PrimateAI
Benign
0.37
T
PROVEAN
Uncertain
-3.3
D;.;.;.
REVEL
Benign
0.075
Sift
Benign
0.060
T;.;.;.
Sift4G
Benign
0.18
T;T;T;T
Polyphen
0.10
B;.;.;B
Vest4
0.12
MVP
0.49
MPC
0.22
ClinPred
0.013
T
GERP RS
3.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.057
gMVP
0.40
Mutation Taster
=88/12
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs76131127; hg19: chr19-50905725; API