4-184659424-T-G

Variant names:

• chr4-184659424-T-G
• rs200857997
• ENST00000515774.5:c.-123T>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 15 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 -8 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001300767.2. 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.265T>G	p.Tyr89Asp	missense	Exon 4 of 14	NP_689896.1	Q96LW4-1
	PRIMPOL	NM_001300767.2		c.-123T>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 13	NP_001287696.1	A0A5S6SZ32
	PRIMPOL	NM_001345894.2		c.-302T>G		5_prime_UTR_premature_start_codon_gain	Exon 4 of 14	NP_001332823.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRIMPOL	ENST00000515774.5	TSL:1	c.-123T>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 13	ENSP00000421913.1	A0A5S6SZ32
	PRIMPOL	ENST00000314970.11	TSL:1 MANE Select	c.265T>G	p.Tyr89Asp	missense	Exon 4 of 14	ENSP00000313816.6	Q96LW4-1
	PRIMPOL	ENST00000512834.5	TSL:1	c.265T>G	p.Tyr89Asp	missense	Exon 4 of 14	ENSP00000425316.1	Q96LW4-2

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

GnomAD2 exomes AF: 0.000442 AC: 111 AN: 251394 AF XY: 0.000368

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00345 AC: 137 AN: 39660

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109022

Other (OTH) AF: 0.000365 AC: 22 AN: 60266

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

African (AFR) AF: 0.00 AC: 0 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00597 AC: 31 AN: 5194

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

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

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000246

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	Myopia 22, autosomal dominant (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.12
Eigen_PC	Benign	0.095
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.96	T
PhyloP100		3.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.27
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.042	D
Polyphen		0.98	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
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs200857997; hg19: chr4-185580578;