19-50414968-C-G

Variant names:

• chr19-50414968-C-G
• rs1555792888
• NM_002691.4:c.2542C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002691.4(POLD1):​c.2542C>G​(p.Leu848Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000208 in 1,441,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. L848M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.65
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

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.2542C>G	p.Leu848Val	missense	Exon 20 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.2620C>G	p.Leu874Val	missense	Exon 19 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.2542C>G	p.Leu848Val	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.2542C>G	p.Leu848Val	missense	Exon 20 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.2620C>G	p.Leu874Val	missense	Exon 20 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.2542C>G	p.Leu848Val	missense	Exon 20 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1441064 Hom.: 0 Cov.: 31 AF XY: 0.00000280 AC XY: 2 AN XY: 715464

African (AFR) AF: 0.00 AC: 0 AN: 32922

American (AMR) AF: 0.00 AC: 0 AN: 42258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25386

East Asian (EAS) AF: 0.00 AC: 0 AN: 38726

South Asian (SAS) AF: 0.00 AC: 0 AN: 84296

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1101112

Other (OTH) AF: 0.0000168 AC: 1 AN: 59358

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.87		Gain of catalytic residue at L848 (P = 0.1171)
MVP		0.65
MPC		1.6
ClinPred		0.99	D
GERP RS		2.5
Varity_R		0.74
gMVP		0.74
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1555792888; hg19: chr19-50918225;