rs745426056

chr19-50416708-G-Achr19-50416708-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_002691.4(POLD1):c.3052G>A(p.Val1018Met) variant causes a missense change. In-silico tool predicts a benign 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. V1018A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.42330757).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.3052G>A	p.Val1018Met	missense_variant	24/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.3052G>A	p.Val1018Met	missense_variant	24/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1387502 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 684976

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ExAC AF: 0.00000993 AC: 1

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

Oct 10, 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. 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 not expected to disrupt POLD1 protein function. ClinVar contains an entry for this variant (Variation ID: 568958). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1018 of the POLD1 protein (p.Val1018Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.33	T;.;.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.27	N
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.5	M;.;.;M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.1	N;.;.;.
REVEL	Benign	0.10
Sift	Benign	0.086	T;.;.;.
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.41	B;.;.;B
Vest4		0.54
MutPred		0.31		Gain of MoRF binding (P = 0.1278);.;.;Gain of MoRF binding (P = 0.1278);
MVP		0.73
MPC		0.68
ClinPred		0.91	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.22
gMVP		0.34

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: rs745426056; hg19: chr19-50919965;