19-50415779-G-T

Variant names:

• chr19-50415779-G-T
• rs746950229
• NM_002691.4:c.2773G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002691.4(POLD1):​c.2773G>T​(p.Val925Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000141 in 1,415,778 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V925M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.01
• Publications: 3 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

ENSG00000142539 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.2773G>T	p.Val925Leu	missense_variant	Exon 22 of 27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.2773G>T	p.Val925Leu	missense_variant	Exon 22 of 27	1	NM_002691.4	ENSP00000406046.1
ENSG00000142539	ENST00000599632.1	c.-21G>T		upstream_gene_variant		5		ENSP00000473233.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1415778 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 700656

African (AFR) AF: 0.00 AC: 0 AN: 32782

American (AMR) AF: 0.00 AC: 0 AN: 39036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24912

East Asian (EAS) AF: 0.00 AC: 0 AN: 38156

South Asian (SAS) AF: 0.00 AC: 0 AN: 80518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4044

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1090704

Other (OTH) AF: 0.00 AC: 0 AN: 58434

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Uncertain:1

Jul 09, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. This variant has not been reported in the literature in individuals with POLD1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 925 of the POLD1 protein (p.Val925Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.;.;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Pathogenic	3.0	M;.;.;M
PhyloP100		6.0
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.9	D;.;.;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D;.;.;.
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		0.95	P;.;.;P
Vest4		0.73
MutPred		0.66		Gain of sheet (P = 0.1945);.;.;Gain of sheet (P = 0.1945);
MVP		0.66
MPC		1.4
ClinPred		0.99	D
GERP RS		3.3
PromoterAI		-0.031	Neutral
Varity_R		0.88
gMVP		0.77
Mutation Taster		=39/61	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: rs746950229; hg19: chr19-50919036; COSMIC: COSV54532135; COSMIC: COSV54532135;