4-184694703-A-G

Position:

• chr4-184694703-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152683.4(PRIMPOL):​c.1607A>G​(p.Glu536Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: PRIMPOL NM_152683.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94

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]

CENPU (HGNC:21348): (centromere protein U) The centromere is a specialized chromatin domain, present throughout the cell cycle, that acts as a platform on which the transient assembly of the kinetochore occurs during mitosis. All active centromeres are characterized by the presence of long arrays of nucleosomes in which CENPA (MIM 117139) replaces histone H3 (see MIM 601128). MLF1IP, or CENPU, is an additional factor required for centromere assembly (Foltz et al., 2006 [PubMed 16622419]).[supplied by OMIM, Mar 2008]

PRIMPOL (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11139402).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRIMPOL	NM_152683.4	c.1607A>G	p.Glu536Gly	missense_variant	14/14	ENST00000314970.11	NP_689896.1
CENPU	NM_024629.4	c.*585T>C		3_prime_UTR_variant	13/13	ENST00000281453.10	NP_078905.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRIMPOL	ENST00000314970.11	c.1607A>G	p.Glu536Gly	missense_variant	14/14	1	NM_152683.4	ENSP00000313816.6
CENPU	ENST00000281453	c.*585T>C		3_prime_UTR_variant	13/13	1	NM_024629.4	ENSP00000281453.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2023

The c.1607A>G (p.E536G) alteration is located in exon 14 (coding exon 12) of the PRIMPOL gene. This alteration results from a A to G substitution at nucleotide position 1607, causing the glutamic acid (E) at amino acid position 536 to be replaced by a glycine (G). 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	0.074
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T;.;T;.
Eigen	Benign	0.075
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.67	.;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.;L;.
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Benign	0.047
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D
Polyphen		0.65	P;P;P;.
Vest4		0.12
MutPred		0.28		Loss of helix (P = 0.0444);.;Loss of helix (P = 0.0444);.;
MVP		0.41
MPC		0.035
ClinPred		0.80	D
GERP RS		3.7
Varity_R		0.12
gMVP		0.11

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-185615857;