19-50403045-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_002691.4(POLD1):c.971-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000148 in 1,554,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

POLD1
NM_002691.4 splice_region, intron

Scores

Splicing: ADA: 0.0001026

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.148

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

POLD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 19-50403045-C-T is Benign according to our data. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50403045-C-T is described in CliVar as Likely_benign. Clinvar id is 469402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4 link	c.971-8C>T		splice_region_variant, intron_variant	Intron 8 of 26	ENST00000440232.7	NP_002682.2	P28340A0A024R4F4Q59FA0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7 link	c.971-8C>T		splice_region_variant, intron_variant	Intron 8 of 26	1	NM_002691.4	ENSP00000406046.1		P28340

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

158552

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1402414

Hom.:

Cov.:

AF XY:

0.0000159

AC XY:

AN XY:

692252

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31740

American (AMR)

AF:

0.00

AC:

AN:

36172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25190

East Asian (EAS)

AF:

0.00

AC:

AN:

36002

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79522

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.0000185

AC:

AN:

1080752

Other (OTH)

AF:

0.0000172

AC:

AN:

58106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Colorectal cancer, susceptibility to, 10

Benign:2

Jun 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 05, 2025

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

not specified

Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.75

(source)

DANN

Benign

0.57

PhyloP100

0.15

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00010

dbscSNV1_RF

Benign

0.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over