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GeneBe

4-184678240-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_152683.4(PRIMPOL):c.853A>G(p.Thr285Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000542 in 1,574,426 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00041 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00056 ( 2 hom. )

Consequence

PRIMPOL
NM_152683.4 missense

Scores

6
9
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.10
Variant links:
Genes affected
PRIMPOL (HGNC:26575): (primase and DNA directed polymerase) This gene encodes a DNA primase-polymerase that belongs to a superfamily of archaeao-eukaryotic primases. Members of this family have primase activity, catalyzing the synthesis of short RNA primers that serve as starting points for DNA synthesis, as well as DNA polymerase activity. The encoded protein facilitates DNA damage tolerance by mediating uninterrupted fork progression after UV irradiation and reinitiating DNA synthesis. An allelic variant in this gene is associated with myopia 22. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAd at 63 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PRIMPOLNM_152683.4 linkuse as main transcriptc.853A>G p.Thr285Ala missense_variant 8/14 ENST00000314970.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PRIMPOLENST00000314970.11 linkuse as main transcriptc.853A>G p.Thr285Ala missense_variant 8/141 NM_152683.4 P4Q96LW4-1

Frequencies

GnomAD3 genomes
AF:
0.000414
AC:
63
AN:
152198
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
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:
0.000750
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000308
AC:
66
AN:
214506
Hom.:
0
AF XY:
0.000256
AC XY:
30
AN XY:
117386
show subpopulations
Gnomad AFR exome
AF:
0.000214
Gnomad AMR exome
AF:
0.000121
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000594
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000555
AC:
790
AN:
1422228
Hom.:
2
Cov.:
28
AF XY:
0.000524
AC XY:
370
AN XY:
706700
show subpopulations
Gnomad4 AFR exome
AF:
0.000191
Gnomad4 AMR exome
AF:
0.0000847
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000573
Gnomad4 NFE exome
AF:
0.000671
Gnomad4 OTH exome
AF:
0.000698
GnomAD4 genome
AF:
0.000414
AC:
63
AN:
152198
Hom.:
1
Cov.:
32
AF XY:
0.000309
AC XY:
23
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.000193
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000750
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000607
Hom.:
0
Bravo
AF:
0.000336
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000228
AC:
1
ESP6500EA
AF:
0.000816
AC:
7
ExAC
AF:
0.000322
AC:
39

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 submitterclinical testingAmbry GeneticsJan 10, 2023The c.853A>G (p.T285A) alteration is located in exon 8 (coding exon 6) of the PRIMPOL gene. This alteration results from a A to G substitution at nucleotide position 853, causing the threonine (T) at amino acid position 285 to be replaced by an alanine (A). 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
Pathogenic
0.73
BayesDel_addAF
Uncertain
0.084
D
BayesDel_noAF
Pathogenic
0.25
Cadd
Uncertain
26
Dann
Uncertain
1.0
DEOGEN2
Benign
0.29
T;.;T;.
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Uncertain
0.96
D
M_CAP
Benign
0.016
T
MetaRNN
Uncertain
0.66
D;D;D;D
MetaSVM
Uncertain
-0.039
T
MutationAssessor
Pathogenic
3.4
M;.;M;M
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-3.5
D;D;D;D
REVEL
Uncertain
0.49
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Uncertain
0.0070
D;D;D;D
Polyphen
1.0
D;.;D;.
Vest4
0.95
MVP
0.65
MPC
0.23
ClinPred
0.52
D
GERP RS
6.0
Varity_R
0.52
gMVP
0.69

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.

Other links and lift over

dbSNP: rs147314180; hg19: chr4-185599394; API