dbSNP rs878854523: POLD1:p.Arg507Cys (chr19-50407007-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002691.4(POLD1):c.1519C>T(p.Arg507Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R507R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.53

Publications

21 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.933

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	HGVSp	Effect	Exon Rank	Protein	UniProt
POLD1	NM_002691.4	MANE Select	c.1519C>T	p.Arg507Cys	missense	Exon 13 of 27	NP_002682.2	P28340
POLD1	NM_001308632.1		c.1519C>T	p.Arg507Cys	missense	Exon 12 of 26	NP_001295561.1	M0R2B7
POLD1	NM_001256849.1		c.1519C>T	p.Arg507Cys	missense	Exon 13 of 27	NP_001243778.1	P28340

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLD1	ENST00000440232.7	TSL:1 MANE Select	c.1519C>T	p.Arg507Cys	missense	Exon 13 of 27	ENSP00000406046.1	P28340
POLD1	ENST00000595904.6	TSL:1	c.1519C>T	p.Arg507Cys	missense	Exon 13 of 27	ENSP00000472445.1	M0R2B7
POLD1	ENST00000599857.7	TSL:1	c.1519C>T	p.Arg507Cys	missense	Exon 13 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

246892

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

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Colorectal cancer, susceptibility to, 10 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

-0.28

MutationAssessor

Pathogenic

4.4

PhyloP100

5.5

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-7.9

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MutPred

0.60

Gain of catalytic residue at L508 (P = 0.0245)

MVP

0.65

MPC

1.9

ClinPred

1.0

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.94

gMVP

0.82

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over