12-56752285-T-G

Position:

• chr12-56752285-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000946.3(PRIM1):​c.14A>C​(p.Asp5Ala) variant causes a missense change. The variant allele was found at a frequency of 0.115 in 1,579,316 control chromosomes in the GnomAD database, including 11,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (1584 hom., cov: 31)
  • Exomes 𝑓: 0.11 (9501 hom.)
• Consequence: PRIM1 NM_000946.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.99

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]

HSD17B6 (HGNC:23316): (hydroxysteroid 17-beta dehydrogenase 6) The protein encoded by this gene has both oxidoreductase and epimerase activities and is involved in androgen catabolism. The oxidoreductase activity can convert 3 alpha-adiol to dihydrotestosterone, while the epimerase activity can convert androsterone to epi-androsterone. Both reactions use NAD+ as the preferred cofactor. This gene is a member of the retinol dehydrogenase family. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016110837).
• BP6: Variant 12-56752285-T-G is Benign according to our data. Variant chr12-56752285-T-G is described in ClinVar as [Benign]. Clinvar id is 1242002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRIM1	NM_000946.3	c.14A>C	p.Asp5Ala	missense_variant	1/13	ENST00000338193.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRIM1	ENST00000338193.11	c.14A>C	p.Asp5Ala	missense_variant	1/13	1	NM_000946.3	P1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 20847 AN: 149232 Hom.: 1584 Cov.: 31

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.0930

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.166

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.141

GnomAD3 exomes AF: 0.124 AC: 24855 AN: 200810 Hom.: 1677 AF XY: 0.122 AC XY: 13248 AN XY: 108188

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.209

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.134

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.112 AC: 160047 AN: 1429966 Hom.: 9501 Cov.: 30 AF XY: 0.112 AC XY: 79326 AN XY: 708726

Gnomad4 AFR exome AF: 0.205

Gnomad4 AMR exome AF: 0.121

Gnomad4 ASJ exome AF: 0.126

Gnomad4 EAS exome AF: 0.212

Gnomad4 SAS exome AF: 0.105

Gnomad4 FIN exome AF: 0.133

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.140 AC: 20869 AN: 149350 Hom.: 1584 Cov.: 31 AF XY: 0.142 AC XY: 10381 AN XY: 73104

Gnomad4 AFR AF: 0.202

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.219

Gnomad4 SAS AF: 0.0941

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.141

Alfa AF: 0.112 Hom.: 2725

Bravo AF: 0.141

TwinsUK AF: 0.0987 AC: 366

ALSPAC AF: 0.107 AC: 413

ESP6500AA AF: 0.181 AC: 705

ESP6500EA AF: 0.0947 AC: 784

ExAC AF: 0.106 AC: 12628

Asia WGS AF: 0.128 AC: 444 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2019	This variant is associated with the following publications: (PMID: 30389748) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0e-37	P;P;P
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.014	D;.
Polyphen		0.99	D;.
Vest4		0.29
MPC		1.1
ClinPred		0.030	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.69
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2277339; hg19: chr12-57146069; COSMIC: COSV57717054; COSMIC: COSV57717054;