rs766784938

chr19-50399472-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_002691.4(POLD1):c.304G>A(p.Asp102Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,459,498 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D102E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.61

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.304G>A	p.Asp102Asn	missense_variant	3/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.304G>A	p.Asp102Asn	missense_variant	3/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251390 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459498 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 726244

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: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2022

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. 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 581360). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. This variant is present in population databases (rs766784938, gnomAD 0.01%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 102 of the POLD1 protein (p.Asp102Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.34
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.;.;.;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.097	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.4	M;.;.;.;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.8	D;.;.;.;.;.
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D;.;.;.;.;.
Sift4G	Uncertain	0.0050	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;D;.
Vest4		0.59
MutPred		0.39		Loss of catalytic residue at D102 (P = 0.0915);Loss of catalytic residue at D102 (P = 0.0915);Loss of catalytic residue at D102 (P = 0.0915);Loss of catalytic residue at D102 (P = 0.0915);Loss of catalytic residue at D102 (P = 0.0915);Loss of catalytic residue at D102 (P = 0.0915);
MVP		0.73
MPC		0.72
ClinPred		0.93	D
GERP RS		4.0
Varity_R		0.59
gMVP		0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs766784938; hg19: chr19-50902729; COSMIC: COSV70954796; COSMIC: COSV70954796;