rs1274522192

Variant names:

• chr4-184661873-T-G
• rs1274522192
• NM_152683.4:c.378T>G

Variant summary

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

The NM_152683.4(PRIMPOL):​c.378T>G​(p.Asp126Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,284 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRIMPOL NM_152683.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.378T>G	p.Asp126Glu	missense	Exon 5 of 14	NP_689896.1	Q96LW4-1
	PRIMPOL	NM_001345891.2		c.378T>G	p.Asp126Glu	missense	Exon 5 of 15	NP_001332820.1
	PRIMPOL	NM_001345892.2		c.378T>G	p.Asp126Glu	missense	Exon 5 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.378T>G	p.Asp126Glu	missense	Exon 5 of 14	ENSP00000313816.6	Q96LW4-1
	PRIMPOL	ENST00000512834.5	TSL:1	c.378T>G	p.Asp126Glu	missense	Exon 5 of 14	ENSP00000425316.1	Q96LW4-2
	PRIMPOL	ENST00000515774.5	TSL:1	c.-10T>G		5_prime_UTR	Exon 4 of 13	ENSP00000421913.1	A0A5S6SZ32

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251170 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461284 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726950

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111638

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.065
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		1.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.63		Loss of ubiquitination at K129 (P = 0.0777)
MVP		0.38
MPC		0.16
ClinPred		0.98	D
GERP RS		-1.0
Varity_R		0.70
gMVP		0.43
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

dbSNP: rs1274522192; hg19: chr4-185583027;