11-67352011-T-C

Position:

chr11-67352011-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_021173.5(POLD4):c.308A>G(p.His103Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000633 in 1,106,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000086 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000061 ( 0 hom. )

Consequence

POLD4
NM_021173.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.59

Variant links:

Genes affected

POLD4 (HGNC:14106): (DNA polymerase delta 4, accessory subunit) This gene encodes the smallest 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. The encoded protein enhances the activity of DNA polymerase delta and plays a role in fork repair and stabilization through interactions with the DNA helicase Bloom syndrome protein. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

POLD4 links:

LOC100130987 (HGNC:):

LOC100130987 links:

RAD9A (HGNC:9827): (RAD9 checkpoint clamp component A) This gene product is highly similar to Schizosaccharomyces pombe rad9, a cell cycle checkpoint protein required for cell cycle arrest and DNA damage repair. This protein possesses 3' to 5' exonuclease activity, which may contribute to its role in sensing and repairing DNA damage. It forms a checkpoint protein complex with RAD1 and HUS1. This complex is recruited by checkpoint protein RAD17 to the sites of DNA damage, which is thought to be important for triggering the checkpoint-signaling cascade. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

RAD9A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4049474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD4	NM_021173.5 linkuse as main transcript	c.308A>G	p.His103Arg	missense_variant	4/4	ENST00000312419.8
LOC100130987	NR_024469.1 linkuse as main transcript	n.423+30678T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD4	ENST00000312419.8 linkuse as main transcript	c.308A>G	p.His103Arg	missense_variant	4/4	1	NM_021173.5	P1	Q9HCU8-1

Frequencies

GnomAD3 genomes

AF:

0.00000858

AC:

AN:

116506

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000331

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000236

AC:

AN:

211518

Hom.:

AF XY:

0.0000266

AC XY:

AN XY:

112822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000250

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000563

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000606

AC:

AN:

989522

Hom.:

Cov.:

AF XY:

0.00000406

AC XY:

AN XY:

492944

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000263

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000322

Gnomad4 NFE exome

AF:

0.00000132

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000858

AC:

AN:

116506

Hom.:

Cov.:

AF XY:

0.0000187

AC XY:

AN XY:

53612

show subpopulations

Gnomad4 AFR

AF:

0.0000331

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000829

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2024

The c.308A>G (p.H103R) alteration is located in exon 4 (coding exon 4) of the POLD4 gene. This alteration results from a A to G substitution at nucleotide position 308, causing the histidine (H) at amino acid position 103 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.027

.;.;T;.;.;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.62

.;.;T;.;T;T

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.40

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.88

N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.6

.;.;N;.;.;.

REVEL

Benign

0.17

Sift

Benign

0.55

.;.;T;.;.;.

Sift4G

Uncertain

0.032

D;D;T;D;D;T

Polyphen

0.77

.;.;P;.;.;.

Vest4

0.50

MutPred

0.69

.;.;Gain of MoRF binding (P = 8e-04);.;.;.;

MVP

0.54

MPC

0.95

ClinPred

0.85

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.62

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