19-50402620-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_002691.4(POLD1):c.849G>T(p.Gln283His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,573,394 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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. Q283R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (22 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (18 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.976

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.

• BP6: Variant 19-50402620-G-T is Benign according to our data. Variant chr19-50402620-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 220697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50402620-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1532/152378) while in subpopulation AFR AF= 0.0349 (1453/41592). AF 95% confidence interval is 0.0334. There are 22 homozygotes in gnomad4. There are 758 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1514 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.849G>T	p.Gln283His	missense_variant	8/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.849G>T	p.Gln283His	missense_variant	8/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes AF: 0.00994 AC: 1514 AN: 152260 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00267 AC: 499 AN: 187218 Hom.: 6 AF XY: 0.00214 AC XY: 215 AN XY: 100482

Gnomad AFR exome AF: 0.0380

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000760

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.000995 AC: 1414 AN: 1421016 Hom.: 18 Cov.: 34 AF XY: 0.000878 AC XY: 617 AN XY: 702946

Gnomad4 AFR exome AF: 0.0357

Gnomad4 AMR exome AF: 0.00229

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000852

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000275

Gnomad4 OTH exome AF: 0.00194

GnomAD4 genome AF: 0.0101 AC: 1532 AN: 152378 Hom.: 22 Cov.: 33 AF XY: 0.0102 AC XY: 758 AN XY: 74514

Gnomad4 AFR AF: 0.0349

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00191 Hom.: 4

Bravo AF: 0.0116

ESP6500AA AF: 0.0324 AC: 142

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.00252 AC: 303

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 03, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Colorectal cancer, susceptibility to, 10 Benign:4

Benign, criteria provided, single submitter	clinical testing	Counsyl	May 26, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 19, 2023	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
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	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2018	This variant is associated with the following publications: (PMID: 26249178) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 26, 2016	Variant summary: The POLD1 c.849G>T (p.Gln283His) variant involves the alteration of a non-conserved nucleotide located at ribonuclease H-like domain of the protein (InterPro). 5/5 in silico tools predict a benign outcome for this variant. This variant was found in 197/33948 control chromosomes (3 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.048913 (189/3864). This frequency is about 3443 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this is likely a common benign polymorphism found primarily in the populations of African origin. In addition, one clinical diagnostic laboratory has classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 31, 2022	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 21, 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. -

Polymerase proofreading-related adenomatous polyposis Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

POLD1, EXON8, c.849G>T, p.Gln283His, Heterozygous, BenignrnThe POLD1 p.Gln283His variant was not identified in the literature. The variant was identified in dbSNP (ID: rs113282414) as "With other allele", and in ClinVar (classified as benign by Invitae, Counsyl, Ambry Genetics and four other submitters; as likely benign by two submitters). The variant was identified in control databases in 787 of 211816 chromosomes (15 homozygous) at a frequency of 0.004 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: African in 713 of 18876 chromosomes (freq: 0.04), Other in 7 of 5358 chromosomes (freq: 0.001), Latino in 59 of 26974 chromosomes (freq: 0.002), European in 8 of 91128 chromosomes (freq: 0.00009); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Gln283 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 this variant meets our laboratory's criteria to be classified as benign.rnAssessment Date: 2019/05/24 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	17
Dann	Benign	0.87
DEOGEN2	Benign	0.12	T;.;.;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.85	D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.0	N;.;.;N
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.75	N;.;.;.
REVEL	Benign	0.059
Sift	Benign	0.29	T;.;.;.
Sift4G	Benign	0.31	T;T;T;T
Polyphen		0.0	B;.;.;B
Vest4		0.27
MutPred		0.42		Loss of ubiquitination at K280 (P = 0.1055);Loss of ubiquitination at K280 (P = 0.1055);Loss of ubiquitination at K280 (P = 0.1055);Loss of ubiquitination at K280 (P = 0.1055);
MVP		0.36
MPC		0.18
ClinPred		0.0037	T
GERP RS		2.1
Varity_R		0.094
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: 7

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

Publications

LitVar

Other links and lift over

dbSNP: rs113282414; hg19: chr19-50905877; COSMIC: COSV70953898; COSMIC: COSV70953898;