chr4-184657173-A-T

Variant names:

• chr4-184657173-A-T
• rs148634809
• NM_152683.4:c.33A>T

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.33A>T​(p.Gln11His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000694 in 1,611,176 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (0 hom.)
• Consequence: PRIMPOL NM_152683.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.337
• Publications: 2 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=0.0041745305).
• BP6: Variant 4-184657173-A-T is Benign according to our data. Variant chr4-184657173-A-T is described in ClinVar as Benign. ClinVar VariationId is 3053134.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 511 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.33A>T	p.Gln11His	missense	Exon 3 of 14	NP_689896.1	Q96LW4-1
	PRIMPOL	NM_001345891.2		c.33A>T	p.Gln11His	missense	Exon 3 of 15	NP_001332820.1
	PRIMPOL	NM_001345892.2		c.33A>T	p.Gln11His	missense	Exon 3 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.33A>T	p.Gln11His	missense	Exon 3 of 14	ENSP00000313816.6	Q96LW4-1
	PRIMPOL	ENST00000512834.5	TSL:1	c.33A>T	p.Gln11His	missense	Exon 3 of 14	ENSP00000425316.1	Q96LW4-2
	PRIMPOL	ENST00000515774.5	TSL:1	c.-207-2167A>T		intron	N/A	ENSP00000421913.1	A0A5S6SZ32

Frequencies

GnomAD3 genomes AF: 0.00332 AC: 505 AN: 152174 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000922 AC: 229 AN: 248444 AF XY: 0.000625

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.000858

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000416 AC: 607 AN: 1458884 Hom.: 0 Cov.: 31 AF XY: 0.000380 AC XY: 276 AN XY: 725714

African (AFR) AF: 0.0113 AC: 378 AN: 33368

American (AMR) AF: 0.000884 AC: 39 AN: 44136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39508

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00313 AC: 18 AN: 5752

European-Non Finnish (NFE) AF: 0.0000999 AC: 111 AN: 1110958

Other (OTH) AF: 0.000979 AC: 59 AN: 60254

GnomAD4 genome AF: 0.00336 AC: 511 AN: 152292 Hom.: 5 Cov.: 32 AF XY: 0.00336 AC XY: 250 AN XY: 74486

African (AFR) AF: 0.0113 AC: 469 AN: 41560

American (AMR) AF: 0.00144 AC: 22 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68010

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00125 Hom.: 1

Bravo AF: 0.00411

ESP6500AA AF: 0.0113 AC: 50

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00105 AC: 127

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000165

EpiControl AF: 0.000179

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PRIMPOL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.0020	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.34
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.090
Sift	Uncertain	0.026	D
Sift4G	Benign	0.14	T
Polyphen		0.017	B
Vest4		0.22
MutPred		0.14		Gain of ubiquitination at K8 (P = 0.1375)
MVP		0.11
MPC		0.038
ClinPred		0.0026	T
GERP RS		-1.2
Varity_R		0.061
gMVP		0.41
Mutation Taster		=93/7	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: rs148634809; hg19: chr4-185578327;