rs749159160

chr19-50416610-G-Achr19-50416610-G-Cchr19-50416610-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002691.4(POLD1):c.2954G>A(p.Arg985Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000994 in 1,408,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R985L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense, splice_region
• Scores: Splicing: ADA: 0.07443
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.09

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01780647).
• BS2: High AC in GnomAdExome at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.2954G>A	p.Arg985Gln	missense_variant, splice_region_variant	24/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.2954G>A	p.Arg985Gln	missense_variant, splice_region_variant	24/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000796 AC: 13 AN: 163266 Hom.: 0 AF XY: 0.000112 AC XY: 10 AN XY: 89118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000418

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000418

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000147

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000994 AC: 14 AN: 1408032 Hom.: 0 Cov.: 34 AF XY: 0.0000129 AC XY: 9 AN XY: 696570

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000347

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: 9.19e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000340

ExAC AF: 0.0000425 AC: 5

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	Jul 27, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31034466) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The POLD1 p.R985Q variant was not identified in the literature nor was it identified in COSMIC. The variant was identified in dbSNP (ID: rs749159160) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 13 of 163266 chromosomes at a frequency of 0.00007962, and was observed at the highest frequency in the Latino population in 11 of 26294 chromosomes (freq: 0.0004183) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.R985 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) 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 in silico or computational prediction software programs (Splice AI exome, dbscSNV Ada, RF) 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. This variant is classified as a variant of uncertain significance. -

Colorectal cancer, susceptibility to, 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 985 of the POLD1 protein (p.Arg985Gln). This variant is present in population databases (rs749159160, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. 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: 408002). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The p.R985Q variant (also known as c.2954G>A) is located in coding exon 23 of the POLD1 gene. The arginine at codon 985 is replaced by glutamine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 23. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.56
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.43	N
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.018	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.;.;L
MutationTaster	Benign	0.82	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.2	N;.;.;.
REVEL	Benign	0.10
Sift	Benign	0.32	T;.;.;.
Sift4G	Benign	0.34	T;T;T;T
Polyphen		0.030	B;.;.;B
Vest4		0.21
MutPred		0.50		Loss of loop (P = 0.0512);.;.;Loss of loop (P = 0.0512);
MVP		0.51
MPC		1.3
ClinPred		0.15	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.074
dbscSNV1_RF	Benign	0.33
SpliceAI score (max)		0.030		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: rs749159160; hg19: chr19-50919867;