rs142122035

Variant names:

• chr4-184661800-T-C
• rs142122035
• NM_152683.4:c.305T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_152683.4(PRIMPOL):​c.305T>C​(p.Val102Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,612,282 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0093 (15 hom., cov: 33)
  • Exomes 𝑓: 0.011 (112 hom.)
• Consequence: PRIMPOL NM_152683.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 7.39
• Publications: 11 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015947789).
• BP6: Variant 4-184661800-T-C is Benign according to our data. Variant chr4-184661800-T-C is described in ClinVar as Benign. ClinVar VariationId is 3350436.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 1413 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.305T>C	p.Val102Ala	missense	Exon 5 of 14	NP_689896.1	Q96LW4-1
	PRIMPOL	NM_001345891.2		c.305T>C	p.Val102Ala	missense	Exon 5 of 15	NP_001332820.1
	PRIMPOL	NM_001345892.2		c.305T>C	p.Val102Ala	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.305T>C	p.Val102Ala	missense	Exon 5 of 14	ENSP00000313816.6	Q96LW4-1
	PRIMPOL	ENST00000512834.5	TSL:1	c.305T>C	p.Val102Ala	missense	Exon 5 of 14	ENSP00000425316.1	Q96LW4-2
	PRIMPOL	ENST00000515774.5	TSL:1	c.-83T>C		5_prime_UTR	Exon 4 of 13	ENSP00000421913.1	A0A5S6SZ32

Frequencies

GnomAD3 genomes AF: 0.00929 AC: 1414 AN: 152218 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00178

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0286

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00933 AC: 2336 AN: 250482 AF XY: 0.00917

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.00716

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0249

Gnomad NFE exome AF: 0.0131

Gnomad OTH exome AF: 0.00917

GnomAD4 exome AF: 0.0108 AC: 15706 AN: 1459946 Hom.: 112 Cov.: 30 AF XY: 0.0104 AC XY: 7583 AN XY: 726386

African (AFR) AF: 0.00120 AC: 40 AN: 33428

American (AMR) AF: 0.00437 AC: 195 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00793 AC: 207 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.000546 AC: 47 AN: 86076

European-Finnish (FIN) AF: 0.0228 AC: 1216 AN: 53378

Middle Eastern (MID) AF: 0.00313 AC: 18 AN: 5758

European-Non Finnish (NFE) AF: 0.0121 AC: 13453 AN: 1110604

Other (OTH) AF: 0.00879 AC: 530 AN: 60310

GnomAD4 genome AF: 0.00928 AC: 1413 AN: 152336 Hom.: 15 Cov.: 33 AF XY: 0.00980 AC XY: 730 AN XY: 74500

African (AFR) AF: 0.00178 AC: 74 AN: 41594

American (AMR) AF: 0.00523 AC: 80 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.0286 AC: 303 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0130 AC: 885 AN: 68024

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.0109 Hom.: 45

Bravo AF: 0.00724

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0116 AC: 100

ExAC AF: 0.00934 AC: 1134

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0112

EpiControl AF: 0.0109

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	PRIMPOL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		7.4
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.87
MVP		0.63
MPC		0.16
ClinPred		0.026	T
GERP RS		5.8
Varity_R		0.60
gMVP		0.64
Mutation Taster		=193/107	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

dbSNP: rs142122035; hg19: chr4-185582954; COSMIC: COSV106100998; COSMIC: COSV106100998;