19-50398931-A-T

Position:

• chr19-50398931-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000440232.7(POLD1):​c.80A>T​(p.Asp27Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,595,608 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D27G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (4 hom.)
• Consequence: POLD1 ENST00000440232.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:16
• Conservation: PhyloP100: 1.10

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037871003).
• BP6: Variant 19-50398931-A-T is Benign according to our data. Variant chr19-50398931-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 245862.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=2, Likely_benign=8}. Variant chr19-50398931-A-T is described in Lovd as [Benign]. Variant chr19-50398931-A-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 248 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.80A>T	p.Asp27Val	missense_variant	2/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.80A>T	p.Asp27Val	missense_variant	2/27	1	NM_002691.4	ENSP00000406046	P1

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 248 AN: 152220 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00301

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00198 AC: 435 AN: 220036 Hom.: 0 AF XY: 0.00194 AC XY: 229 AN XY: 117768

Gnomad AFR exome AF: 0.000440

Gnomad AMR exome AF: 0.000717

Gnomad ASJ exome AF: 0.00345

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000577

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00270 AC: 3903 AN: 1443270 Hom.: 4 Cov.: 33 AF XY: 0.00260 AC XY: 1862 AN XY: 716064

Gnomad4 AFR exome AF: 0.000361

Gnomad4 AMR exome AF: 0.000600

Gnomad4 ASJ exome AF: 0.00317

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00109

Gnomad4 NFE exome AF: 0.00328

Gnomad4 OTH exome AF: 0.00178

GnomAD4 genome AF: 0.00163 AC: 248 AN: 152338 Hom.: 1 Cov.: 32 AF XY: 0.00154 AC XY: 115 AN XY: 74500

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00301

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00258 Hom.: 1

Bravo AF: 0.00181

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00214 AC: 259

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:16

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 07, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 07, 2023	- -

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	POLD1: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 10, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Aug 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 05, 2019	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 07, 2020	- -

Colorectal cancer, susceptibility to, 10 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Polymerase proofreading-related adenomatous polyposis Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The POLD1 p.Asp27Val variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs150066950), ClinVar (classified with conflicting interpretations of pathogenicity; benign by Invitae and Ambry Genetics, likely benign by GeneDx, Mendelics, Prevention Genetics, Praxis fuer Humangenetick Tuebingen Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen, and uncertain significance by Quest Diagnostics Nichols Institute San Juan Capistrano and True Health Diagnostics). Ambry reports co-occurence with a mutation in another gene that clearly explains a proband's phenotype (ClinVar, SCV000670890.2).The variant was identified in control databases in 485 of 251414 chromosomes (1 homozygous) at a frequency of 0.001929, and was observed at the highest frequency in the European population in 394 of 113670 chromosomes (freq: 0.003466) (Genome Aggregation Database March 6, 2019, v2.1.1).The p.Asp27 residue is not conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) 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 (Splice AI exome) do not predict a deleterious effect on 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Uncertain	0.61	D;.;.;.;D;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.80	.;.;T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0038	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N;.;.;.;N;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.2	D;.;.;.;.;.
REVEL	Benign	0.060
Sift	Uncertain	0.013	D;.;.;.;.;.
Sift4G	Uncertain	0.036	D;D;D;D;D;D
Polyphen		0.028	B;.;.;.;B;.
Vest4		0.24
MVP		0.52
MPC		0.35
ClinPred		0.029	T
GERP RS		3.3
Varity_R		0.17
gMVP		0.36

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: rs150066950; hg19: chr19-50902188;