NM_021173.5:c.308A>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 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. 13/21 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

Publications

0 publications found

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:

ENSG00000256514 (HGNC:):

ENSG00000256514 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 was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021173.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLD4	NM_021173.5	MANE Select	c.308A>G	p.His103Arg	missense	Exon 4 of 4	NP_066996.3
POLD4	NM_001256870.2		c.196A>G	p.Ile66Val	missense	Exon 3 of 3	NP_001243799.1	Q9HCU8-2
POLD4	NR_046411.2		n.464A>G		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLD4	ENST00000312419.8	TSL:1 MANE Select	c.308A>G	p.His103Arg	missense	Exon 4 of 4	ENSP00000311368.3	Q9HCU8-1
ENSG00000256514	ENST00000543494.1	TSL:3	c.227A>G	p.His76Arg	missense	Exon 4 of 4	ENSP00000480527.1	A0A087WWV3
POLD4	ENST00000530584.5	TSL:1	c.83A>G	p.His28Arg	missense	Exon 4 of 4	ENSP00000436361.2	E9PL15

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

GnomAD2 exomes

AF:

0.0000236

AC:

AN:

211518

AF XY:

0.0000266

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 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

African (AFR)

AF:

0.00

AC:

AN:

22116

American (AMR)

AF:

0.00

AC:

AN:

32976

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15142

East Asian (EAS)

AF:

0.000263

AC:

AN:

15184

South Asian (SAS)

AF:

0.00

AC:

AN:

75012

European-Finnish (FIN)

AF:

0.0000322

AC:

AN:

31080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3284

European-Non Finnish (NFE)

AF:

0.00000132

AC:

AN:

758146

Other (OTH)

AF:

0.00

AC:

AN:

36582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000858

AC:

AN:

116506

Hom.:

Cov.:

AF XY:

0.0000187

AC XY:

AN XY:

53612

show subpopulations

African (AFR)

AF:

0.0000331

AC:

AN:

30230

American (AMR)

AF:

0.00

AC:

AN:

8612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3206

East Asian (EAS)

AF:

0.00

AC:

AN:

3444

South Asian (SAS)

AF:

0.00

AC:

AN:

3278

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4302

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

60738

Other (OTH)

AF:

0.00

AC:

AN:

1584

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000829

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.027

Eigen

Benign

0.15

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.62

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.40

MetaSVM

Benign

-1.0

PhyloP100

3.6

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.6

REVEL

Benign

0.17

Sift

Benign

0.55

Sift4G

Uncertain

0.032

Polyphen

0.77

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

Mutation Taster

=60/40

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over