chr19-50417924-C-G

Position:

• chr19-50417924-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002691.4(POLD1):​c.3301C>G​(p.Pro1101Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.09

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]

ENSG00000142539 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.106806844).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.3301C>G	p.Pro1101Ala	missense_variant	27/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.3301C>G	p.Pro1101Ala	missense_variant	27/27	1	NM_002691.4	ENSP00000406046.1
ENSG00000142539	ENST00000599632.1	c.425+655C>G		intron_variant		5		ENSP00000473233.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 15, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1371060). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1101 of the POLD1 protein (p.Pro1101Ala). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2023

The p.P1101A variant (also known as c.3301C>G), located in coding exon 26 of the POLD1 gene, results from a C to G substitution at nucleotide position 3301. The proline at codon 1101 is replaced by alanine, an amino acid with highly similar properties. 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	0.057
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Benign	0.81
DEOGEN2	Benign	0.14	T;.;.;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.78	.;.;T;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.34	N;.;.;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.45	N;.;.;.
REVEL	Benign	0.061
Sift	Benign	0.62	T;.;.;.
Sift4G	Benign	0.84	T;T;T;T
Polyphen		0.0070	B;.;.;B
Vest4		0.41
MutPred		0.21		Loss of glycosylation at P1101 (P = 0.0242);.;.;Loss of glycosylation at P1101 (P = 0.0242);
MVP		0.27
MPC		0.61
ClinPred		0.065	T
GERP RS		2.8
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.14
gMVP		0.17

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: rs142223599; hg19: chr19-50921181;