NM_002691.4:c.2563C>A

Variant names:

• chr19-50414989-C-A
• rs768048535
• NM_002691.4:c.2563C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_002691.4(POLD1):​c.2563C>A​(p.Arg855Arg) variant causes a splice region, synonymous 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R855R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLD1 NM_002691.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0002749
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0540
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 19-50414989-C-A is Benign according to our data. Variant chr19-50414989-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 484342.
• BP7: Synonymous conserved (PhyloP=-0.054 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	NM_002691.4	MANE Select	c.2563C>A	p.Arg855Arg	splice_region synonymous	Exon 20 of 27	NP_002682.2
	POLD1	NM_001308632.1		c.2641C>A	p.Arg881Arg	splice_region synonymous	Exon 19 of 26	NP_001295561.1
	POLD1	NM_001256849.1		c.2563C>A	p.Arg855Arg	splice_region synonymous	Exon 20 of 27	NP_001243778.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	ENST00000440232.7	TSL:1 MANE Select	c.2563C>A	p.Arg855Arg	splice_region synonymous	Exon 20 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.2641C>A	p.Arg881Arg	splice_region synonymous	Exon 20 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.2563C>A	p.Arg855Arg	splice_region synonymous	Exon 20 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: 1420166 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 703594

African (AFR) AF: 0.00 AC: 0 AN: 32368

American (AMR) AF: 0.00 AC: 0 AN: 39646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24610

East Asian (EAS) AF: 0.00 AC: 0 AN: 37712

South Asian (SAS) AF: 0.00 AC: 0 AN: 81804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5604

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090460

Other (OTH) AF: 0.00 AC: 0 AN: 58480

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Colorectal cancer, susceptibility to, 10 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.7
DANN	Benign	0.69
PhyloP100		-0.054
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.22
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs768048535; hg19: chr19-50918246;