NM_002691.4:c.2397C>G

Variant names:

• chr19-50414823-C-G
• rs878854535
• NM_002691.4:c.2397C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002691.4(POLD1):​c.2397C>G​(p.Phe799Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,425,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F799F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.838
• 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: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3364377).

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.2397C>G	p.Phe799Leu	missense	Exon 20 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.2475C>G	p.Phe825Leu	missense	Exon 19 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.2397C>G	p.Phe799Leu	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.2397C>G	p.Phe799Leu	missense	Exon 20 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.2475C>G	p.Phe825Leu	missense	Exon 20 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.2397C>G	p.Phe799Leu	missense	Exon 20 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1425178 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 705864

African (AFR) AF: 0.00 AC: 0 AN: 32472

American (AMR) AF: 0.00 AC: 0 AN: 41392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24236

East Asian (EAS) AF: 0.00 AC: 0 AN: 38340

South Asian (SAS) AF: 0.00 AC: 0 AN: 81272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090714

Other (OTH) AF: 0.0000171 AC: 1 AN: 58616

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.33	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.84
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.12
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.054	T
Polyphen		0.018	B
Vest4		0.19
MutPred		0.52		Loss of sheet (P = 0.0817)
MVP		0.52
MPC		1.2
ClinPred		0.99	D
GERP RS		0.025
Varity_R		0.81
gMVP		0.65
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs878854535; hg19: chr19-50918080;