19-50417940-C-A

Variant names:

• chr19-50417940-C-A
• rs1555793944
• NM_002691.4:c.3317C>A

Variant summary

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

The NM_002691.4(POLD1):​c.3317C>A​(p.Ala1106Asp) 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. 13/21 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0580

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=0.16555312).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.3317C>A	p.Ala1106Asp	missense_variant	Exon 27 of 27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.3317C>A	p.Ala1106Asp	missense_variant	Exon 27 of 27	1	NM_002691.4	ENSP00000406046.1
ENSG00000142539	ENST00000599632.1	c.425+671C>A		intron_variant	Intron 5 of 9	5		ENSP00000473233.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450034 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 721182

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Jan 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 855398). 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 alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1106 of the POLD1 protein (p.Ala1106Asp). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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

Jun 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A1106D variant (also known as c.3317C>A), located in coding exon 26 of the POLD1 gene, results from a C to A substitution at nucleotide position 3317. The alanine at codon 1106 is replaced by aspartic acid, an amino acid with dissimilar 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	0.076
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.30	T;.;.;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.70	.;.;T;T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.34	N;.;.;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.2	N;.;.;.
REVEL	Benign	0.060
Sift	Benign	0.097	T;.;.;.
Sift4G	Benign	0.57	T;T;T;T
Polyphen		0.013	B;.;.;B
Vest4		0.42
MutPred		0.16		Loss of catalytic residue at A1106 (P = 0.0236);.;.;Loss of catalytic residue at A1106 (P = 0.0236);
MVP		0.56
MPC		1.2
ClinPred		0.45	T
GERP RS		3.3
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.29
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1555793944; hg19: chr19-50921197;