rs137953986

chr19-50401894-G-Achr19-50401894-G-Cchr19-50401894-G-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.433G>A(p.Ala145Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00268 in 1,613,944 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 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. A145D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (6 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 3.72

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=0.011245161).
• BP6: Variant 19-50401894-G-A is Benign according to our data. Variant chr19-50401894-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 221138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50401894-G-A is described in Lovd as [Benign]. Variant chr19-50401894-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 364 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.433G>A	p.Ala145Thr	missense_variant	4/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.433G>A	p.Ala145Thr	missense_variant	4/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152038 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00265

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00268 AC: 674 AN: 251270 Hom.: 4 AF XY: 0.00264 AC XY: 359 AN XY: 135812

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00199

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.00276

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00271 AC: 3967 AN: 1461788 Hom.: 6 Cov.: 35 AF XY: 0.00268 AC XY: 1948 AN XY: 727218

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00194

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.00270

Gnomad4 OTH exome AF: 0.00233

GnomAD4 genome AF: 0.00239 AC: 364 AN: 152156 Hom.: 1 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74382

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0126

Gnomad4 NFE AF: 0.00265

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00210 Hom.: 0

Bravo AF: 0.00152

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00254 AC: 308

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	POLD1: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2019	This variant is associated with the following publications: (PMID: 21796119, 28608266) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 15, 2023	- -
Likely 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.433G>A (p.Ala145Thr) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant is located in the Ribonuclease H-like domain (InterPro).This variant was found in 308/121298 control chromosomes (2 homozygotes), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.012269 (81/6602). This frequency is about 864 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. In a non-peer reviewed project report this variant was reported to be found in 3/95 CRC patients (Rypdal KB, 2015). Another missense change at the same residue p.A145D has also been found in one CRC patient who did not have somatic pathogenic variants (PMID 23263490). Although it is not monogenically linked to CRC phenotype based on population data, whether this variant represents a risk allele needs to be further examined by case-control studies. There are no published functional studies. In ClinVar, while one clinical lab classifies it as uncertain significance, another as benign. Taken together, this variant is currently classified as likely benign. -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 09, 2018	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Colorectal cancer, susceptibility to, 10 Benign:2

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	- -

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

Nov 04, 2021

- -

Familial ovarian cancer Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The POLD1 p.Ala145Thr variant was not identified in the literature. The variant was identified in dbSNP (ID: rs137953986 as "With Likely benign allele"), ClinVar (classified as benign by Invitae; and as likely benign by Ambry Genetics, GeneDx and four other submitters), and in LOVD 3.0 (2x as benign and likely benign). The variant was identified in control databases in 767 of 276920 chromosomes (4 homozygous) at a frequency of 0.003, 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 7 of 23990 chromosomes (freq: 0.0003), Other in 13 of 6454 chromosomes (freq: 0.002), Latino in 5 of 34416 chromosomes (freq: 0.0002), European in 340 of 126504 chromosomes (freq: 0.003), Ashkenazi Jewish in 1 of 10134 chromosomes (freq: 0.0001), East Asian in 1 of 18866 chromosomes (freq: 0.00005), Finnish in 341 of 25774 chromosomes (freq: 0.01), and South Asian in 59 of 30782 chromosomes (freq: 0.002). The p.Ala145 residue is conserved in mammals but not in more distantly related organisms. However, four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2018

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. -

Colon cancer Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Aug 01, 2016

Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 47 year old with a history of colon cancer diagnosed at 47 and a family history of colon cancer. In exonuclease domain. -

POLD1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 14, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	17
Dann	Benign	0.94
DEOGEN2	Benign	0.10	T;.;.;.;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.48	N;.;.;.;N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.42	N;.;.;.;.
REVEL	Benign	0.096
Sift	Benign	0.61	T;.;.;.;.
Sift4G	Benign	0.73	T;T;D;T;T
Polyphen		0.068	B;.;.;.;B
Vest4		0.52
MVP		0.43
MPC		0.20
ClinPred		0.0094	T
GERP RS		4.0
Varity_R		0.10
gMVP		0.38

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

LitVar

Other links and lift over

dbSNP: rs137953986; hg19: chr19-50905151;