19-50417867-C-T

Position:

• chr19-50417867-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP3_Moderate PP5 BS2

The ENST00000440232.7(POLD1):​c.3244C>T​(p.Arg1082Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,456,778 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1082G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: POLD1 ENST00000440232.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.830

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936
• PP5: Variant 19-50417867-C-T is Pathogenic according to our data. Variant chr19-50417867-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 537091.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.3244C>T	p.Arg1082Cys	missense_variant	27/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.3244C>T	p.Arg1082Cys	missense_variant	27/27	1	NM_002691.4	ENSP00000406046	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1456778 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 724244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Combined immunodeficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Sep 19, 2024

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, (MDPL; MIM#15381), and combined immunodeficiency, MONDO:0015131, POLD1-related. It is the suspected mechanism of colorectal cancer, susceptibility to, 10, (MIM#612591). Variants causing MDPL have retained exonuclease activity (PMID: 30023403, 31750734). (I) 0108 - This gene is associated with both recessive and dominant disease. Monoallelic variants have been identified in patients with MDPL (ClinVar, PMID: 23770608). Biallelic variants have been recently identified in two families with combined immunodeficiency, MONDO:0015131, POLD1-related (PMID: 31629014, 31449058). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0601 - Variant is located in the well-established functional zinc finger domain (DECIPHER). It introduces a novel cysteine residue, which are critical residues in these domains (PMID: 31278166). (SP) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Alternative changes to glycine, leucine, histidine and proline have all been reported as VUS (ClinVar). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (NM_002691.3(PLOD1):c.2251-1G>C) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (testing by the Broad Institute). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Colorectal cancer, susceptibility to, 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 28, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1082 of the POLD1 protein (p.Arg1082Cys). 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: 537091). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLD1 protein function with a positive predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D;.;.;D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Benign	0.69	D
LIST_S2	Pathogenic	1.0	.;.;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Pathogenic	4.1	H;.;.;H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.8	D;.;.;.
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.73
MutPred		0.72		Gain of methylation at K1083 (P = 0.0136);.;.;Gain of methylation at K1083 (P = 0.0136);
MVP		0.86
MPC		1.9
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.99
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1307047144; hg19: chr19-50921124; COSMIC: COSV54532693; COSMIC: COSV54532693;