19-50402116-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002691.4(POLD1):c.581C>G(p.Ser194Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000455 in 1,611,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. S194F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.894

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011740446).
• BP6: Variant 19-50402116-C-G is Benign according to our data. Variant chr19-50402116-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 239356.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=2}.
• BS2: High AC in GnomAd at 88 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.581C>G	p.Ser194Cys	missense_variant	5/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.581C>G	p.Ser194Cys	missense_variant	5/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00423

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000581 AC: 144 AN: 247890 Hom.: 0 AF XY: 0.000619 AC XY: 83 AN XY: 133980

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000531

Gnomad FIN exome AF: 0.00346

Gnomad NFE exome AF: 0.000438

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.000442 AC: 645 AN: 1459304 Hom.: 0 Cov.: 34 AF XY: 0.000452 AC XY: 328 AN XY: 725802

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: 0.000559

Gnomad4 FIN exome AF: 0.00424

Gnomad4 NFE exome AF: 0.000312

Gnomad4 OTH exome AF: 0.000365

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74484

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00423

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000510 Hom.: 1

Bravo AF: 0.000193

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000618 AC: 75

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 28, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2020	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 28, 2024	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

See cases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 21, 2022

ACMG categories: BS2,BP4 -

Colorectal cancer, susceptibility to, 10 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The POLD1 p.Ser194Cys variant was not identified in the literature. The variant was identified in dbSNP (ID: rs144656348) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae, GeneDx and two other submitters; as uncertain significance by Ambry Genetics), and in LOVD 3.0 (1x) .The variant was identified in control databases in 178 of 273686 chromosomes (1 homozygous) at a frequency of 0.0007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 8 of 6358 chromosomes (freq: 0.001), Latino in 1 of 34170 chromosomes (freq: 0.00003), European in 68 of 124668 chromosomes (freq: 0.0006), European Finnish in 84 of 25520 chromosomes (freq: 0.003), and South Asian in 17 of 30346 chromosomes (freq: 0.0006), while the variant was not observed in the African, Ashkenazi Jewish, and East Asian, populations. The p.Ser194 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.30	T;.;.;.;T
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.28	N
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;.;.;L
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.0	N;.;.;.;.
REVEL	Benign	0.045
Sift	Benign	0.16	T;.;.;.;.
Sift4G	Benign	0.11	T;T;D;T;T
Polyphen		0.89	P;.;.;.;P
Vest4		0.37
MVP		0.66
MPC		0.48
ClinPred		0.073	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.51

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: rs144656348; hg19: chr19-50905373;