rs1555793399

Variant names:

• chr19-50416607-CA-C
• rs1555793399
• NM_002691.4:c.2954-2delA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_002691.4(POLD1):​c.2954-2delA variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: POLD1 NM_002691.4 splice_acceptor, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.91

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 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03429603 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.2954-2delA		splice_acceptor_variant, intron_variant	Intron 23 of 26	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.2954-2delA		splice_acceptor_variant, intron_variant	Intron 23 of 26	1	NM_002691.4	ENSP00000406046.1
ENSG00000142539	ENST00000599632.1	c.161-2delA		splice_acceptor_variant, intron_variant	Intron 2 of 9	5		ENSP00000473233.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Apr 17, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer, susceptibility to, 10 Uncertain:1

Apr 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a splice site in intron 23 of the POLD1 gene. Missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLD1 protein are associated with PPAP (polymerase proofreading–associated polyposis) (PMID: 23263490, 23447401). However, loss-of-function variants that result in an absent or severely disrupted POLD1 protein, and missense variants outside the exonuclease domain, are unlikely to be associated with PPAP. This variant is not present in population databases (gnomAD no frequency). 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: 484362). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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

Jan 06, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2954-2delA intronic variant, results from a deletion of one nucleotide two nucleotides upstream from coding exon 23 of the POLD1 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6411 samples (12822 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 25000 alleles tested) in our clinical cohort. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. As neither this specific alteration nor loss of function as a mechanism of pathogenicity have been well-described in the POLD1 gene, the clinical significance of this variant remains unknown (ACMG Standards and guidelines for the interpretation of sequence variants. Genet Med. 2015 May; 17(5):405-23). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555793399; hg19: chr19-50919864;