chr4-184659424-T-G

Variant names:

• chr4-184659424-T-G
• rs200857997
• ENST00000515774:c.-123T>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001300767.2(PRIMPOL):​c.-123T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,610,904 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: PRIMPOL NM_001300767.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:2
• Conservation: PhyloP100: 3.54

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019212097).
• BS2: High AC in GnomAd4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRIMPOL	NM_152683.4	c.265T>G	p.Tyr89Asp	missense_variant	Exon 4 of 14	ENST00000314970.11	NP_689896.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRIMPOL	ENST00000314970.11	c.265T>G	p.Tyr89Asp	missense_variant	Exon 4 of 14	1	NM_152683.4	ENSP00000313816.6

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152262 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: 0.00615

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000442 AC: 111 AN: 251394 Hom.: 0 AF XY: 0.000368 AC XY: 50 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00565

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000125 AC: 182 AN: 1458524 Hom.: 1 Cov.: 28 AF XY: 0.000107 AC XY: 78 AN XY: 725792

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00345

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.000365

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152380 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74524

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00597

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000146 Hom.: 0

Bravo AF: 0.000246

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Myopia 22, autosomal dominant Pathogenic:1 Uncertain:1

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

NM_152683.3:c.265T>G in PRIMPOL gene has an allele frequency of 0.006 in East Asian subpopulation in the gnomAD database. The PRIMPOL gene is also known as CCDC111. Variants in the PRIMPOL gene is inherited as a dominant model. Since the phenotype (high myopia) is not lethal. The frequency in the genomAD cannot rule out its pathogenicity. Zhao et al reported a pedigree, both patient with high myopia and normal family memebers of which harbors this variant. It is suggested to be not full penetrance (PMID: 23579484). We interpret it as variant of uncertain significance (VUS). -

Aug 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Uncertain:1

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.095
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.67	.;T;T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.019	T;T;T
MetaSVM	Benign	-0.96	T
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.042	D;D;D
Polyphen		0.98	D;D;.
Vest4		0.90
MVP		0.35
MPC		0.18
ClinPred		0.16	T
GERP RS		3.0
Varity_R		0.89
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs200857997; hg19: chr4-185580578;