19-50414894-G-A

Position:

• chr19-50414894-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000440232.7(POLD1):​c.2468G>A​(p.Arg823His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000687 in 1,456,414 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R823C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: POLD1 ENST00000440232.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.78

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24728528).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.2468G>A	p.Arg823His	missense_variant	20/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.2468G>A	p.Arg823His	missense_variant	20/27	1	NM_002691.4	ENSP00000406046	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 247728 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 134010

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000589

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000687 AC: 10 AN: 1456414 Hom.: 0 Cov.: 31 AF XY: 0.00000828 AC XY: 6 AN XY: 724242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000631

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 21, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Colorectal cancer, susceptibility to, 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 05, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 823 of the POLD1 protein (p.Arg823His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 660883). 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 with a negative 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	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;.;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.29	N
LIST_S2	Pathogenic	0.99	.;.;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;.;L
MutationTaster	Benign	0.63	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.2	D;.;.;.
REVEL	Benign	0.063
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		0.041	B;.;.;B
Vest4		0.28
MutPred		0.64		Gain of methylation at K827 (P = 0.043);.;.;Gain of methylation at K827 (P = 0.043);
MVP		0.50
MPC		1.3
ClinPred		0.94	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.54

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: rs771734704; hg19: chr19-50918151; COSMIC: COSV54532451; COSMIC: COSV54532451;