4-184659424-T-G
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2
The NM_152683.4(PRIMPOL):c.265T>G(p.Tyr89Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,610,904 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 1 hom. )
Consequence
PRIMPOL
NM_152683.4 missense
NM_152683.4 missense
Scores
1
7
9
Clinical Significance
Conservation
PhyloP100: 3.54
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 -6 ACMG points.
PM1
?
In a mutagenesis_site Reduced DNA primase activity. (size 0) in uniprot entity PRIPO_HUMAN
BP4
?
Computational evidence support a benign effect (MetaRNN=0.019212097).
BS2
?
High AC in GnomAd at 39 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRIMPOL | NM_152683.4 | c.265T>G | p.Tyr89Asp | missense_variant | 4/14 | ENST00000314970.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRIMPOL | ENST00000314970.11 | c.265T>G | p.Tyr89Asp | missense_variant | 4/14 | 1 | NM_152683.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000256 AC: 39AN: 152262Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000442 AC: 111AN: 251394Hom.: 0 AF XY: 0.000368 AC XY: 50AN XY: 135882
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GnomAD4 exome AF: 0.000125 AC: 182AN: 1458524Hom.: 1 Cov.: 28 AF XY: 0.000107 AC XY: 78AN XY: 725792
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GnomAD4 genome ? AF: 0.000249 AC: 38AN: 152380Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22AN XY: 74524
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Myopia 22, autosomal dominant Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2013 | - - |
Uncertain significance, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | NM_152683.3:c.265T>G in PRIMPOL gene has an allele frequency of 0.006 in East Asian subpopulation in the gnomAD database. The PRIMPOL gene is also known as CCDC111. Variants in the PRIMPOL gene is inherited as a dominant model. Since the phenotype (high myopia) is not lethal. The frequency in the genomAD cannot rule out its pathogenicity. Zhao et al reported a pedigree, both patient with high myopia and normal family memebers of which harbors this variant. It is suggested to be not full penetrance (PMID: 23579484). We interpret it as variant of uncertain significance (VUS). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Benign
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at