12-56741516-A-G

Position:

• chr12-56741516-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000946.3(PRIM1):​c.901T>C​(p.Cys301Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRIM1 NM_000946.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 8.86

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant 12-56741516-A-G is Pathogenic according to our data. Variant chr12-56741516-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 981922.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRIM1	NM_000946.3	c.901T>C	p.Cys301Arg	missense_variant	9/13	ENST00000338193.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRIM1	ENST00000338193.11	c.901T>C	p.Cys301Arg	missense_variant	9/13	1	NM_000946.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Microcephalic primordial dwarfism Pathogenic:1

Pathogenic, no assertion criteria provided

in vitro;research

MRC Institute of Genetics and Molecular Medicine, University of Edinburgh

Sep 01, 2020

- -

Primordial dwarfism-immunodeficiency-lipodystrophy syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.6	M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.1	D;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.013	D;D;D
Sift4G	Uncertain	0.047	D;D;.
Polyphen		0.99	D;.;.
Vest4		0.92
MutPred		0.79		Gain of catalytic residue at M297 (P = 0.0014);.;.;
MVP		0.73
MPC		1.6
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.95
gMVP		0.88

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: rs1953871835; hg19: chr12-57135300;