rs200931999

chr19-50413456-G-Achr19-50413456-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_002691.4(POLD1):c.2185G>A(p.Glu729Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,613,218 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E729Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 8.59

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=0.41840267).
• BP6: Variant 19-50413456-G-A is Benign according to our data. Variant chr19-50413456-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 414802.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=3}.
• BS2: High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.2185G>A	p.Glu729Lys	missense_variant	18/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.2185G>A	p.Glu729Lys	missense_variant	18/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000156 AC: 39 AN: 249648 Hom.: 0 AF XY: 0.000163 AC XY: 22 AN XY: 134978

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.000234

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.0000582 AC: 85 AN: 1461028 Hom.: 0 Cov.: 31 AF XY: 0.0000647 AC XY: 47 AN XY: 726764

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000188

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74340

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000736 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.000222 AC: 27

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 31, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2023	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; This variant is associated with the following publications: (PMID: 20951805) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	POLD1: BS1 -

Colorectal cancer, susceptibility to, 10 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 22, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Apr 06, 2018	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;.;.;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.4	M;.;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.6	D;.;.;.
REVEL	Benign	0.23
Sift	Benign	0.030	D;.;.;.
Sift4G	Uncertain	0.051	T;D;D;T
Polyphen		0.88	P;.;.;P
Vest4		0.64
MutPred		0.63		Gain of MoRF binding (P = 0.002);.;.;Gain of MoRF binding (P = 0.002);
MVP		0.70
MPC		1.7
ClinPred		0.41	T
GERP RS		4.3
Varity_R		0.70
gMVP		0.95

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: rs200931999; hg19: chr19-50916713; COSMIC: COSV70956727; COSMIC: COSV70956727;