rs3218772

chr19-50398939-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002691.4(POLD1):c.88C>T(p.Arg30Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,593,262 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R30Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0071 (8 hom., cov: 32)
  • Exomes 𝑓: 0.011 (124 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.865

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070928633).
• BP6: Variant 19-50398939-C-T is Benign according to our data. Variant chr19-50398939-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 221163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50398939-C-T is described in Lovd as [Benign]. Variant chr19-50398939-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 1085 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.88C>T	p.Arg30Trp	missense_variant	2/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.88C>T	p.Arg30Trp	missense_variant	2/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes AF: 0.00713 AC: 1085 AN: 152206 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00621

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00821 AC: 1770 AN: 215634 Hom.: 11 AF XY: 0.00887 AC XY: 1023 AN XY: 115286

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00649

Gnomad ASJ exome AF: 0.00806

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0111

Gnomad FIN exome AF: 0.00271

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0108 AC: 15496 AN: 1440938 Hom.: 124 Cov.: 33 AF XY: 0.0108 AC XY: 7736 AN XY: 714662

Gnomad4 AFR exome AF: 0.00238

Gnomad4 AMR exome AF: 0.00694

Gnomad4 ASJ exome AF: 0.00794

Gnomad4 EAS exome AF: 0.0000512

Gnomad4 SAS exome AF: 0.0119

Gnomad4 FIN exome AF: 0.00302

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.00712 AC: 1085 AN: 152324 Hom.: 8 Cov.: 32 AF XY: 0.00648 AC XY: 483 AN XY: 74486

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00932

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.0117

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.0107 Hom.: 19

Bravo AF: 0.00713

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.0140 AC: 120

ExAC AF: 0.00707 AC: 856

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 05, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 25, 2016	Variant summary: The c.88C>T (p.Arg30Trp) in POLD1 gene is a missense change that involves a non-conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at an overall frequency 0.013 (671/52972 chrs tested) including 5 homozygotes. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000142). The variant was identified in a clinical case, which also carried a known pathogenic mutation, c.68_69delAG, in BRCA1 gene. The variant is cited as Benign by a reputable database/clinical laboratory. Taking together, the variant was classified as Benign. -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The POLD1 p.Arg30Trp variant was identified in 1 of 58 proband chromosomes (frequency: 0.02) from individuals or families with HNPCC (Talseth-Palmer 2015). The variant was also identified in dbSNP (ID: rs3218772) as "With Benign allele", ClinVar (classified as benign by Invitae, Counsyl, GeneDx, Ambry Genetics and three other clinical laboratories), Cosmic (1x in prostate tissue), and MutDB. The variant was identified in control databases in 1935 of 241054 chromosomes (13 homozygous) at a frequency of 0.008, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1228 of 108476 chromosomes (freq: 0.01), South Asian in 299 of 26820 chromosomes (freq: 0.01), African in 28 of 21060 chromosomes (freq: 0.001), Other in 62 of 5816 chromosomes (freq: 0.01), Latino in 183 of 30048 chromosomes (freq: 0.006), Ashkenazi Jewish in 74 of 9266 chromosomes (freq: 0.0079), and Finnish in 61 of 22694 chromosomes (freq: 0.0026), while the variant was not observed in the East Asian population. The p.Arg30 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	POLD1: BP4, BS1, BS2 -

Colorectal cancer, susceptibility to, 10 Benign:3

Benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 10, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 20, 2015	This alteration is classified as 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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 01, 2017	- -

Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;.;.;T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.079	N
MetaRNN	Benign	0.0071	T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.34	N;.;.;.;N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.38	N;.;.;.;.;.
REVEL	Benign	0.028
Sift	Benign	0.043	D;.;.;.;.;.
Sift4G	Uncertain	0.047	D;D;T;D;D;T
Polyphen		0.95	P;.;.;.;P;.
Vest4		0.29
MVP		0.51
MPC		0.29
ClinPred		0.0043	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.041
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3218772; hg19: chr19-50902196; COSMIC: COSV70955632; COSMIC: COSV70955632;