rs878854538

Variant names:

• chr19-50414941-C-A
• rs878854538
• NM_002691.4:c.2515C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50414941-C-A
• chr19-50414941-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002691.4(POLD1):​c.2515C>A​(p.Leu839Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,502 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L839V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.52
• 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):

• mandibular hypoplasia-deafness-progeroid syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P, Orphanet
• 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2515C>A	p.Leu839Ile	missense	Exon 20 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.2593C>A	p.Leu865Ile	missense	Exon 19 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.2515C>A	p.Leu839Ile	missense	Exon 20 of 27	NP_001243778.1	P28340

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	ENST00000440232.7	TSL:1 MANE Select	c.2515C>A	p.Leu839Ile	missense	Exon 20 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.2593C>A	p.Leu865Ile	missense	Exon 20 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.2515C>A	p.Leu839Ile	missense	Exon 20 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456502 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724208

African (AFR) AF: 0.00 AC: 0 AN: 33372

American (AMR) AF: 0.00 AC: 0 AN: 44320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39458

South Asian (SAS) AF: 0.00 AC: 0 AN: 85820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108972

Other (OTH) AF: 0.00 AC: 0 AN: 60132

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Colorectal cancer, susceptibility to, 10 (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.71	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.60
MutPred		0.69		Loss of disorder (P = 0.3297)
MVP		0.61
MPC		1.7
ClinPred		0.98	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.67
gMVP		0.48
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs878854538; hg19: chr19-50918198;