19-50416540-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002691.4(POLD1):c.2953+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.636 in 1,549,824 control chromosomes in the GnomAD database, including 327,237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 25596 hom., cov: 34)

Exomes 𝑓: 0.65 ( 301641 hom. )

Consequence

POLD1
NM_002691.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.631

Publications

12 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 19-50416540-C-T is Benign according to our data. Variant chr19-50416540-C-T is described in ClinVar as Benign. ClinVar VariationId is 258788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002691.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
POLD1	NM_002691.4	MANE Select	c.2953+12C>T	intron	N/A	NP_002682.2
POLD1	NM_001308632.1		c.3031+12C>T	intron	N/A	NP_001295561.1
POLD1	NM_001256849.1		c.2953+12C>T	intron	N/A	NP_001243778.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
POLD1	ENST00000440232.7	TSL:1 MANE Select	c.2953+12C>T	intron	N/A	ENSP00000406046.1
POLD1	ENST00000595904.6	TSL:1	c.3031+12C>T	intron	N/A	ENSP00000472445.1
POLD1	ENST00000599857.7	TSL:1	c.2953+12C>T	intron	N/A	ENSP00000473052.1

Frequencies

GnomAD3 genomes

AF:

0.552

AC:

83965

AN:

152096

Hom.:

25590

Cov.:

show subpopulations

Gnomad AFR

AF:

0.329

Gnomad AMI

AF:

0.598

Gnomad AMR

AF:

0.643

Gnomad ASJ

AF:

0.509

Gnomad EAS

AF:

0.140

Gnomad SAS

AF:

0.439

Gnomad FIN

AF:

0.692

Gnomad MID

AF:

0.566

Gnomad NFE

AF:

0.687

Gnomad OTH

AF:

0.540

GnomAD2 exomes

AF:

0.582

AC:

89666

AN:

154134

AF XY:

0.574

show subpopulations

Gnomad AFR exome

AF:

0.327

Gnomad AMR exome

AF:

0.702

Gnomad ASJ exome

AF:

0.516

Gnomad EAS exome

AF:

0.136

Gnomad FIN exome

AF:

0.685

Gnomad NFE exome

AF:

0.686

Gnomad OTH exome

AF:

0.610

GnomAD4 exome

AF:

0.645

AC:

901856

AN:

1397608

Hom.:

301641

Cov.:

AF XY:

0.640

AC XY:

441424

AN XY:

690068

show subpopulations

African (AFR)

AF:

0.320

AC:

10194

AN:

31842

American (AMR)

AF:

0.697

AC:

25311

AN:

36306

Ashkenazi Jewish (ASJ)

AF:

0.514

AC:

12938

AN:

25158

East Asian (EAS)

AF:

0.117

AC:

4227

AN:

36070

South Asian (SAS)

AF:

0.453

AC:

36016

AN:

79550

European-Finnish (FIN)

AF:

0.687

AC:

30204

AN:

43952

Middle Eastern (MID)

AF:

0.563

AC:

2934

AN:

5210

European-Non Finnish (NFE)

AF:

0.690

AC:

745708

AN:

1081470

Other (OTH)

AF:

0.591

AC:

34324

AN:

58050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

17764

35528

53293

71057

88821

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18958

37916

56874

75832

94790

<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:

0.552

AC:

83985

AN:

152216

Hom.:

25596

Cov.:

AF XY:

0.550

AC XY:

40943

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.328

AC:

13633

AN:

41544

American (AMR)

AF:

0.643

AC:

9837

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.509

AC:

1766

AN:

3472

East Asian (EAS)

AF:

0.140

AC:

723

AN:

5178

South Asian (SAS)

AF:

0.439

AC:

2124

AN:

4834

European-Finnish (FIN)

AF:

0.692

AC:

7352

AN:

10620

Middle Eastern (MID)

AF:

0.585

AC:

172

AN:

294

European-Non Finnish (NFE)

AF:

0.687

AC:

46703

AN:

67950

Other (OTH)

AF:

0.535

AC:

1130

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1770

3540

5309

7079

8849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

704

1408

2112

2816

3520

<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:

0.610

Hom.:

5292

Bravo

AF:

0.539

Asia WGS

AF:

0.301

AC:

1051

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Colorectal cancer, susceptibility to, 10 (2)

Hereditary cancer-predisposing syndrome (1)

Mandibular hypoplasia-deafness-progeroid syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.9

(source)

DANN

Benign

0.86

PhyloP100

0.63

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over