rs757190258

Positions:

• chr19-50416682-G-A
• chr19-50416682-G-C
• chr19-50416682-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002691.4(POLD1):​c.3026G>A​(p.Arg1009His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 1,399,418 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.32

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]

ENSG00000142539 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22438613).
• BS2: High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.3026G>A	p.Arg1009His	missense_variant	24/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.3026G>A	p.Arg1009His	missense_variant	24/27	1	NM_002691.4	ENSP00000406046.1
ENSG00000142539	ENST00000599632.1	c.233G>A	p.Arg78His	missense_variant	3/10	5		ENSP00000473233.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000334 AC: 5 AN: 149668 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 81562

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000837

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000200 AC: 28 AN: 1399418 Hom.: 0 Cov.: 34 AF XY: 0.0000188 AC XY: 13 AN XY: 691792

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000249

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000113

ExAC AF: 0.0000178 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32686686, 19296856) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 16, 2018	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 05, 2024

Variant summary: POLD1 c.3026G>A (p.Arg1009His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 149668 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3026G>A has been reported in the literature in at least one individual with a personal or family history of breast cancer (Mur_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32792570). ClinVar contains an entry for this variant (Variation ID: 469320). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Colorectal cancer, susceptibility to, 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1009 of the POLD1 protein (p.Arg1009His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 469320). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLD1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;.;.;D
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.93	.;.;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	3.0	M;.;.;M
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.5	D;.;.;.
REVEL	Benign	0.16
Sift	Benign	0.047	D;.;.;.
Sift4G	Uncertain	0.053	T;T;T;T
Polyphen		0.91	P;.;.;P
Vest4		0.25
MutPred		0.68		Loss of MoRF binding (P = 0.0377);.;.;Loss of MoRF binding (P = 0.0377);
MVP		0.49
MPC		0.78
ClinPred		0.52	D
GERP RS		-0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.56
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs757190258; hg19: chr19-50919939;