NM_152683.4:c.219T>C

Variant names:

• chr4-184659378-T-C
• rs201904312
• NM_152683.4:c.219T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_152683.4(PRIMPOL):​c.219T>C​(p.Asp73Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: PRIMPOL NM_152683.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.03
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 4-184659378-T-C is Benign according to our data. Variant chr4-184659378-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 723431.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.03 with no splicing effect.
• BS2: High AC in GnomAd4 at 5 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.219T>C	p.Asp73Asp	synonymous	Exon 4 of 14	NP_689896.1	Q96LW4-1
	PRIMPOL	NM_001345891.2		c.219T>C	p.Asp73Asp	synonymous	Exon 4 of 15	NP_001332820.1
	PRIMPOL	NM_001345892.2		c.219T>C	p.Asp73Asp	synonymous	Exon 4 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.219T>C	p.Asp73Asp	synonymous	Exon 4 of 14	ENSP00000313816.6	Q96LW4-1
	PRIMPOL	ENST00000512834.5	TSL:1	c.219T>C	p.Asp73Asp	synonymous	Exon 4 of 14	ENSP00000425316.1	Q96LW4-2
	PRIMPOL	ENST00000515774.5	TSL:1	c.-169T>C		5_prime_UTR	Exon 3 of 13	ENSP00000421913.1	A0A5S6SZ32

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152228 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: 0.000576

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000835 AC: 21 AN: 251364 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461704 Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13 AN XY: 727164

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000681 AC: 27 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111902

Other (OTH) AF: 0.000182 AC: 11 AN: 60380

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74512

African (AFR) AF: 0.0000481 AC: 2 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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: 0.00 Hom.: 0

Bravo AF: 0.0000340

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely 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
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.4
DANN	Benign	0.46
PhyloP100		1.0

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: rs201904312; hg19: chr4-185580532;