rs368965066

Variant names:

• chr19-50415719-C-G
• rs368965066
• NM_002691.4:c.2718-5C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-50415719-C-G
• chr19-50415719-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002691.4(POLD1):​c.2718-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,384,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 splice_region, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.540
• Publications: 0 publications found

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]

POLD1 Gene-Disease associations (from GenCC):

• POLD1-related polyposis and colorectal cancer syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• colorectal cancer, susceptibility to, 10

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• mandibular hypoplasia-deafness-progeroid syndrome

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
• Polymerase proofreading-related adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• immunodeficiency 120

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• non-severe combined immunodeficiency due to polymerase delta deficiency

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000142539 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.2718-5C>G		splice_region_variant, intron_variant	Intron 21 of 26	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.2718-5C>G		splice_region_variant, intron_variant	Intron 21 of 26	1	NM_002691.4	ENSP00000406046.1
ENSG00000142539	ENST00000599632.1	c.-81C>G		upstream_gene_variant		5		ENSP00000473233.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1384054 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 683728

African (AFR) AF: 0.00 AC: 0 AN: 31946

American (AMR) AF: 0.00 AC: 0 AN: 35906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25020

East Asian (EAS) AF: 0.0000274 AC: 1 AN: 36506

South Asian (SAS) AF: 0.00 AC: 0 AN: 79258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4048

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1072600

Other (OTH) AF: 0.00 AC: 0 AN: 57516

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Uncertain:1

Jun 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1026093). 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 falls in intron 21 of the POLD1 gene. It does not directly change the encoded amino acid sequence of the POLD1 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	24
DANN	Benign	0.91
PhyloP100		0.54
PromoterAI		0.024	Neutral
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.96		Position offset: 1
DS_AL_spliceai		0.50		Position offset: 5

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

Other links and lift over

dbSNP: rs368965066; hg19: chr19-50918976;