chr19-50398953-C-G

Variant names:

• chr19-50398953-C-G
• rs754716741
• NM_002691.4:c.102C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002691.4(POLD1):​c.102C>G​(p.Phe34Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000628 in 1,433,610 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F34I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -3.17
• Publications: 7 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14282814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.102C>G	p.Phe34Leu	missense_variant	Exon 2 of 27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.102C>G	p.Phe34Leu	missense_variant	Exon 2 of 27	1	NM_002691.4	ENSP00000406046.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000628 AC: 9 AN: 1433610 Hom.: 0 Cov.: 33 AF XY: 0.00000282 AC XY: 2 AN XY: 710314

African (AFR) AF: 0.00 AC: 0 AN: 33154

American (AMR) AF: 0.00 AC: 0 AN: 39728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25468

East Asian (EAS) AF: 0.00 AC: 0 AN: 38850

South Asian (SAS) AF: 0.00 AC: 0 AN: 82088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4524

European-Non Finnish (NFE) AF: 0.00000819 AC: 9 AN: 1098866

Other (OTH) AF: 0.00 AC: 0 AN: 59340

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Uncertain:1

Dec 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 34 of the POLD1 protein (p.Phe34Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 841478). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F34L variant (also known as c.102C>G), located in coding exon 1 of the POLD1 gene, results from a C to G substitution at nucleotide position 102. The phenylalanine at codon 34 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	2.5
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.;.;.;D;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.67	.;.;T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.14	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.;.;.;N;.
PhyloP100		-3.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.4	D;.;.;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.098	T;.;.;.;.;.
Sift4G	Benign	0.18	T;T;D;T;T;D
Polyphen		0.30	B;.;.;.;B;.
Vest4		0.26
MutPred		0.33		Loss of helix (P = 0.0795);Loss of helix (P = 0.0795);Loss of helix (P = 0.0795);Loss of helix (P = 0.0795);Loss of helix (P = 0.0795);Loss of helix (P = 0.0795);
MVP		0.44
MPC		0.22
ClinPred		0.31	T
GERP RS		-5.0
PromoterAI		0.010	Neutral
Varity_R		0.16
gMVP		0.41
Mutation Taster		=54/46	polymorphism

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: rs754716741; hg19: chr19-50902210;