NM_152683.4:c.502C>T

Variant names:

• chr4-184666010-C-T
• rs541152487
• NM_152683.4:c.502C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_152683.4(PRIMPOL):​c.502C>T​(p.Arg168Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 1,608,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: PRIMPOL NM_152683.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 53 AD gene.

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.502C>T	p.Arg168Trp	missense	Exon 6 of 14	NP_689896.1	Q96LW4-1
	PRIMPOL	NM_001345894.2		c.-195C>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 14	NP_001332823.1
	PRIMPOL	NM_001345897.2		c.-195C>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 13	NP_001332826.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRIMPOL	ENST00000314970.11	TSL:1 MANE Select	c.502C>T	p.Arg168Trp	missense	Exon 6 of 14	ENSP00000313816.6	Q96LW4-1
	PRIMPOL	ENST00000512834.5	TSL:1	c.502C>T	p.Arg168Trp	missense	Exon 6 of 14	ENSP00000425316.1	Q96LW4-2
	PRIMPOL	ENST00000515774.5	TSL:1	c.115C>T	p.Arg39Trp	missense	Exon 5 of 13	ENSP00000421913.1	A0A5S6SZ32

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152044 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000639 AC: 16 AN: 250374 AF XY: 0.0000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000875

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000364 AC: 53 AN: 1456818 Hom.: 0 Cov.: 27 AF XY: 0.0000414 AC XY: 30 AN XY: 725042

African (AFR) AF: 0.00 AC: 0 AN: 33358

American (AMR) AF: 0.000112 AC: 5 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39620

South Asian (SAS) AF: 0.000256 AC: 22 AN: 85780

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1108146

Other (OTH) AF: 0.0000830 AC: 5 AN: 60210

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74378

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41522

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000568638), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000577 AC: 7

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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	Benign	0.33
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.60
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Uncertain	0.71	D
PhyloP100		2.3
Sift4G	Uncertain	0.012	D
Vest4		0.62
MVP		0.59
GERP RS		4.2
Varity_R		0.33
gMVP		0.80
Mutation Taster		=4/196	disease causing (fs/PTC)

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

dbSNP: rs541152487; hg19: chr4-185587164;