chr19-50403217-C-T

Variant names:

• chr19-50403217-C-T
• rs1064794926
• NM_002691.4:c.1135C>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.1135C>T​(p.Gln379*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Q379Q) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLD1 NM_002691.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.952
• 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

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002691.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	NM_002691.4	MANE Select	c.1135C>T	p.Gln379*	stop_gained splice_region	Exon 9 of 27	NP_002682.2
	POLD1	NM_001308632.1		c.1135C>T	p.Gln379*	stop_gained splice_region	Exon 8 of 26	NP_001295561.1
	POLD1	NM_001256849.1		c.1135C>T	p.Gln379*	stop_gained splice_region	Exon 9 of 27	NP_001243778.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	ENST00000440232.7	TSL:1 MANE Select	c.1135C>T	p.Gln379*	stop_gained splice_region	Exon 9 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.1135C>T	p.Gln379*	stop_gained splice_region	Exon 9 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.1135C>T	p.Gln379*	stop_gained splice_region	Exon 9 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1399138 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 689742

African (AFR) AF: 0.00 AC: 0 AN: 31980

American (AMR) AF: 0.00 AC: 0 AN: 36188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24692

East Asian (EAS) AF: 0.00 AC: 0 AN: 36518

South Asian (SAS) AF: 0.00 AC: 0 AN: 79636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078058

Other (OTH) AF: 0.00 AC: 0 AN: 57856

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

May 25, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted POLD1 c.1135C>T at the cDNA level and p.Gln379Ter (Q379X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to result in protein truncation or nonsense-mediated mRNA decay. This variant has not, to our knowledge, been published in the literature. While some missense variants in POLD1 have been recognized as an underlying cause of Polymerase Proofreading-Associated Polyposis (PPAP), there are no data at this time to support that loss-of-function variants confer the same cancer risks. We therefore consider POLD1 Gln379Ter to be a variant of uncertain significance with respect to cancer.

Colorectal cancer, susceptibility to, 10 Uncertain:1

Jul 06, 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 create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 421125). 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 creates a premature translational stop signal (p.Gln379*) in the POLD1 gene. Missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLD1 protein are associated with an increased risk for colonic adenomatous polyps and colon cancer (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 polyposis or colon cancer.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	58
DANN	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		0.95
Vest4		0.92
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=5/195	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
Splicevardb		3.0
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.95		Position offset: -2

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

Other links and lift over

dbSNP: rs1064794926; hg19: chr19-50906474;