chr4-184657144-A-G

Variant names:

• chr4-184657144-A-G
• NM_152683.4:c.4A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152683.4(PRIMPOL):​c.4A>G​(p.Asn2Asp) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRIMPOL NM_152683.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.70
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1545664).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152683.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRIMPOL	NM_152683.4	MANE Select	c.4A>G	p.Asn2Asp	missense	Exon 3 of 14	NP_689896.1	Q96LW4-1
	PRIMPOL	NM_001345891.2		c.4A>G	p.Asn2Asp	missense	Exon 3 of 15	NP_001332820.1
	PRIMPOL	NM_001345892.2		c.4A>G	p.Asn2Asp	missense	Exon 3 of 15	NP_001332821.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRIMPOL	ENST00000314970.11	TSL:1 MANE Select	c.4A>G	p.Asn2Asp	missense	Exon 3 of 14	ENSP00000313816.6	Q96LW4-1
	PRIMPOL	ENST00000512834.5	TSL:1	c.4A>G	p.Asn2Asp	missense	Exon 3 of 14	ENSP00000425316.1	Q96LW4-2
	PRIMPOL	ENST00000515774.5	TSL:1	c.-207-2196A>G		intron	N/A	ENSP00000421913.1	A0A5S6SZ32

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	PRIMPOL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.00097	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.055
Sift	Benign	0.42	T
Sift4G	Benign	0.21	T
Polyphen		0.051	B
Vest4		0.14
MutPred		0.16		Gain of ubiquitination at K4 (P = 0.0544)
MVP		0.21
MPC		0.036
ClinPred		0.25	T
GERP RS		0.37
Varity_R		0.060
gMVP		0.17
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

hg19: chr4-185578298;