rs569395274

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BP6

The NM_002691.4(POLD1):c.3218+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000505 in 1,583,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

POLD1
NM_002691.4 splice_region, intron

Scores

Splicing: ADA: 0.9963

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: -0.776

Publications

1 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:

ENSG00000142539 (HGNC:):

ENSG00000142539 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.

BP6

Variant 19-50417274-G-A is Benign according to our data. Variant chr19-50417274-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 239334.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4 link	c.3218+5G>A		splice_region_variant, intron_variant	Intron 26 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.3218+5G>A		splice_region_variant, intron_variant	Intron 26 of 26	1	NM_002691.4	ENSP00000406046.1		P28340
ENSG00000142539	ENST00000599632.1 link	c.425+5G>A		splice_region_variant, intron_variant	Intron 5 of 9	5		ENSP00000473233.1		M0R3H8

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152182

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:

0.00212

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000199

AC:

AN:

211304

AF XY:

0.000172

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000313

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00212

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000104

Gnomad OTH exome

AF:

0.000186

GnomAD4 exome

AF:

0.0000468

AC:

AN:

1431152

Hom.:

Cov.:

AF XY:

0.0000507

AC XY:

AN XY:

710434

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32918

American (AMR)

AF:

0.0000233

AC:

AN:

42856

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25680

East Asian (EAS)

AF:

0.00129

AC:

AN:

38798

South Asian (SAS)

AF:

0.000131

AC:

AN:

83946

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5652

European-Non Finnish (NFE)

AF:

0.00000273

AC:

AN:

1099636

Other (OTH)

AF:

0.0000337

AC:

AN:

59316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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:

0.0000854

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41574

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00212

AC:

AN:

5178

South Asian (SAS)

AF:

0.000414

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.000144

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jan 16, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports a deleterious effect on splicing; Observed in an individual with breast cancer (PMID: 32091409); This variant is associated with the following publications: (PMID: 32091409) -

Mar 21, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mandibular hypoplasia-deafness-progeroid syndrome

Uncertain:1

Aug 13, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Mar 12, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3218+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 25 in the POLD1 gene. This nucleotide position is not conserved on limited sequence alignment. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the available evidence, the clinical significance of this alteration remains unclear. -

Colorectal cancer, susceptibility to, 10

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.84

CADD

Pathogenic

(source)

DANN

Benign

0.73

PhyloP100

-0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Benign

0.64

SpliceAI score (max)

0.91

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.91

Position offset: -3

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over