rs3219433

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002691.4(POLD1):c.2718-12A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0087 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000032 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

POLD1
NM_002691.4 intron

Scores

Splicing: ADA: 0.00001998

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.90

Publications

10 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):

mandibular hypoplasia-deafness-progeroid syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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 -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

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	UniProt
POLD1	NM_002691.4	MANE Select	c.2718-12A>C	intron	N/A	NP_002682.2	P28340
POLD1	NM_001308632.1		c.2796-12A>C	intron	N/A	NP_001295561.1	M0R2B7
POLD1	NM_001256849.1		c.2718-12A>C	intron	N/A	NP_001243778.1	P28340

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
POLD1	ENST00000440232.7	TSL:1 MANE Select	c.2718-12A>C	intron	N/A	ENSP00000406046.1	P28340
POLD1	ENST00000595904.6	TSL:1	c.2796-12A>C	intron	N/A	ENSP00000472445.1	M0R2B7
POLD1	ENST00000599857.7	TSL:1	c.2718-12A>C	intron	N/A	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes

AF:

0.00873

AC:

533

AN:

61056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00316

Gnomad AMI

AF:

0.0145

Gnomad AMR

AF:

0.00830

Gnomad ASJ

AF:

0.00781

Gnomad EAS

AF:

0.00226

Gnomad SAS

AF:

0.00341

Gnomad FIN

AF:

0.0159

Gnomad MID

AF:

0.00794

Gnomad NFE

AF:

0.0209

Gnomad OTH

AF:

0.00358

GnomAD2 exomes

AF:

0.000169

AC:

AN:

118132

AF XY:

0.000155

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000500

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000117

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000221

Gnomad OTH exome

AF:

0.000595

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000323

AC:

AN:

896936

Hom.:

Cov.:

AF XY:

0.0000246

AC XY:

AN XY:

446350

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

28984

American (AMR)

AF:

0.0000363

AC:

AN:

27566

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15844

East Asian (EAS)

AF:

0.00

AC:

AN:

19430

South Asian (SAS)

AF:

0.0000619

AC:

AN:

64652

European-Finnish (FIN)

AF:

0.000108

AC:

AN:

18436

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2594

European-Non Finnish (NFE)

AF:

0.0000322

AC:

AN:

683740

Other (OTH)

AF:

0.00

AC:

AN:

35690

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.230

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00871

AC:

533

AN:

61182

Hom.:

Cov.:

AF XY:

0.00824

AC XY:

246

AN XY:

29842

show subpopulations

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

African (AFR)

AF:

0.00315

AC:

100

AN:

31764

American (AMR)

AF:

0.00830

AC:

AN:

5182

Ashkenazi Jewish (ASJ)

AF:

0.00781

AC:

AN:

1152

East Asian (EAS)

AF:

0.00225

AC:

AN:

1776

South Asian (SAS)

AF:

0.00341

AC:

AN:

2344

European-Finnish (FIN)

AF:

0.0159

AC:

AN:

1696

Middle Eastern (MID)

AF:

0.00877

AC:

AN:

114

European-Non Finnish (NFE)

AF:

0.0208

AC:

334

AN:

16022

Other (OTH)

AF:

0.00350

AC:

AN:

856

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.268

Heterozygous variant carriers

117

175

234

292

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:

0.000212

Hom.:

488

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.40

(source)

DANN

Benign

0.65

PhyloP100

-1.9

PromoterAI

0.043

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000020

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Computational scores

Splicing

Publications

Other links and lift over