12-56746131-C-G

Variant names:

• chr12-56746131-C-G
• rs757181601
• NM_000946.3:c.493G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000946.3(PRIM1):​c.493G>C​(p.Val165Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V165I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRIM1 NM_000946.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.96
• Publications: 1 publications found

Genes affected

PRIM1 (HGNC:9369): (DNA primase subunit 1) The replication of DNA in eukaryotic cells is carried out by a complex chromosomal replication apparatus, in which DNA polymerase alpha and primase are two key enzymatic components. Primase, which is a heterodimer of a small subunit and a large subunit, synthesizes small RNA primers for the Okazaki fragments made during discontinuous DNA replication. The protein encoded by this gene is the small, 49 kDa primase subunit. [provided by RefSeq, Jul 2008]

PRIM1 Gene-Disease associations (from GenCC):

• primordial dwarfism-immunodeficiency-lipodystrophy syndrome

  Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000946.3. 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
	PRIM1	NM_000946.3	MANE Select	c.493G>C	p.Val165Leu	missense	Exon 5 of 13	NP_000937.1	P49642

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRIM1	ENST00000338193.11	TSL:1 MANE Select	c.493G>C	p.Val165Leu	missense	Exon 5 of 13	ENSP00000350491.5	P49642
	PRIM1	ENST00000672280.1		c.493G>C	p.Val165Leu	missense	Exon 5 of 14	ENSP00000500157.1	A0A5F9ZHB6
	PRIM1	ENST00000706567.1		c.493G>C	p.Val165Leu	missense	Exon 5 of 12	ENSP00000516452.1	A0A9L9PXM3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.21
Sift	Benign	0.057	T
Sift4G	Uncertain	0.029	D
Polyphen		0.10	B
Vest4		0.60
MutPred		0.70		Gain of catalytic residue at W168 (P = 0)
MVP		0.36
MPC		0.54
ClinPred		0.97	D
GERP RS		5.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.81
gMVP		0.70
Mutation Taster		=41/59	disease causing

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: rs757181601; hg19: chr12-57139915;