19-50415778-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7

The NM_002691.4(POLD1):c.2772C>T(p.Tyr924Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000299 in 1,571,172 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

POLD1
NM_002691.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.0100

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 19-50415778-C-T is Benign according to our data. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420. Variant chr19-50415778-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 391420.

BP7

Synonymous conserved (PhyloP=0.01 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4 link	c.2772C>T	p.Tyr924Tyr	synonymous_variant	Exon 22 of 27	ENST00000440232.7	NP_002682.2	P28340A0A024R4F4Q59FA0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7 link	c.2772C>T	p.Tyr924Tyr	synonymous_variant	Exon 22 of 27	1	NM_002691.4	ENSP00000406046.1		P28340
ENSG00000142539	ENST00000599632.1 link	c.-22C>T		upstream_gene_variant		5		ENSP00000473233.1		M0R3H8

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151794

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:

0.000195

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000266

AC:

AN:

187922

AF XY:

0.0000198

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000333

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000282

AC:

AN:

1419260

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

702590

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32900

American (AMR)

AF:

0.0000254

AC:

AN:

39300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25058

East Asian (EAS)

AF:

0.000209

AC:

AN:

38326

South Asian (SAS)

AF:

0.00

AC:

AN:

80708

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47448

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4062

European-Non Finnish (NFE)

AF:

0.0000275

AC:

AN:

1092844

Other (OTH)

AF:

0.0000171

AC:

AN:

58614

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.0000461

AC:

AN:

151912

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.000196

AC:

AN:

5112

South Asian (SAS)

AF:

0.000208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000736

AC:

AN:

67898

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

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:

0.0000222

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome;C5935622:Immunodeficiency 120

Uncertain:1

Apr 18, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 21, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

POLD1-related disorder

Benign:1

May 09, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

not provided

Benign:1

Mar 07, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Colorectal cancer, susceptibility to, 10

Benign:1

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Jul 06, 2015

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

0.010

PromoterAI

-0.0077

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over