rs780604625

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002691.4(POLD1):c.353C>T(p.Ser118Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,613,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. S118T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1O:1

Conservation

PhyloP100: 1.64

Variant links:

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]

POLD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.117854744).

BS2

High AC in GnomAd at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4 linkuse as main transcript	c.353C>T	p.Ser118Phe	missense_variant	4/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7 linkuse as main transcript	c.353C>T	p.Ser118Phe	missense_variant	4/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000842

AC:

AN:

249266

Hom.:

AF XY:

0.0000666

AC XY:

AN XY:

135134

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000941

Gnomad NFE exome

AF:

0.0000534

Gnomad OTH exome

AF:

0.000820

GnomAD4 exome

AF:

0.0000712

AC:

104

AN:

1461258

Hom.:

Cov.:

AF XY:

0.0000702

AC XY:

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000755

Gnomad4 NFE exome

AF:

0.0000711

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000151

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000901

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer (Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 27121473, 29349598, 35264596) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 23, 2019	- -

Colorectal cancer, susceptibility to, 10

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jun 21, 2021	ACMG classification criteria: PS4 supporting, BP4 supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 118 of the POLD1 protein (p.Ser118Phe). This variant is present in population databases (rs780604625, gnomAD 0.02%). 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: 239345). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2023

The p.S118F variant (also known as c.353C>T), located in coding exon 3 of the POLD1 gene, results from a C to T substitution at nucleotide position 353. The serine at codon 118 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Mandibular hypoplasia-deafness-progeroid syndrome

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Uncertain significance and reported on 01-30-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.43

Cadd

Benign

Dann

Benign

0.90

DEOGEN2

Uncertain

0.67

D;.;.;.;D

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.19

M_CAP

Benign

0.019

MetaRNN

Benign

0.12

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.9

L;.;.;.;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.9

D;.;.;.;.

REVEL

Benign

0.099

Sift

Benign

0.051

T;.;.;.;.

Sift4G

Uncertain

0.043

D;D;D;D;D

Polyphen

0.14

B;.;.;.;B

Vest4

0.27

MutPred

0.28

Loss of disorder (P = 0.0091);Loss of disorder (P = 0.0091);Loss of disorder (P = 0.0091);Loss of disorder (P = 0.0091);Loss of disorder (P = 0.0091);

MVP

0.42

MPC

0.23

ClinPred

0.064

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.072

gMVP

0.32

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over