rs17876047

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000505.4(F12):c.711C>T(p.Pro237Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,608,338 control chromosomes in the GnomAD database, including 749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 62 hom., cov: 33)

Exomes 𝑓: 0.028 ( 687 hom. )

Consequence

F12
NM_000505.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.389

Variant links:

Genes affected

F12 (HGNC:3530): (coagulation factor XII) This gene encodes coagulation factor XII which circulates in blood as a zymogen. This single chain zymogen is converted to a two-chain serine protease with an heavy chain (alpha-factor XIIa) and a light chain. The heavy chain contains two fibronectin-type domains, two epidermal growth factor (EGF)-like domains, a kringle domain and a proline-rich domain, whereas the light chain contains only a catalytic domain. On activation, further cleavages takes place in the heavy chain, resulting in the production of beta-factor XIIa light chain and the alpha-factor XIIa light chain becomes beta-factor XIIa heavy chain. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then to beta-factor XIIa. The active factor XIIa participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. It activates coagulation factors VII and XI. Defects in this gene do not cause any clinical symptoms and the sole effect is that whole-blood clotting time is prolonged. [provided by RefSeq, Jul 2008]

F12 links:

GRK6 (HGNC:4545): (G protein-coupled receptor kinase 6) This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase subfamily of the Ser/Thr protein kinase family. The protein phosphorylates the activated forms of G protein-coupled receptors thus initiating their deactivation. Several transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

GRK6 links:

F12 (HGNC:):

F12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 5-177404588-G-A is Benign according to our data. Variant chr5-177404588-G-A is described in ClinVar as [Benign]. Clinvar id is 352999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177404588-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.389 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0229 (3491/152214) while in subpopulation NFE AF= 0.0321 (2184/67974). AF 95% confidence interval is 0.031. There are 62 homozygotes in gnomad4. There are 1727 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 62 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F12	NM_000505.4 linkuse as main transcript	c.711C>T	p.Pro237Pro	synonymous_variant	8/14	ENST00000253496.4	NP_000496.2	P00748Q8IZZ5
F12	XM_011534462.3 linkuse as main transcript	c.375C>T	p.Pro125Pro	synonymous_variant	5/11		XP_011532764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F12	ENST00000253496.4 linkuse as main transcript	c.711C>T	p.Pro237Pro	synonymous_variant	8/14	1	NM_000505.4	ENSP00000253496.3		P00748

Frequencies

GnomAD3 genomes

AF:

0.0230

AC:

3493

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0192

Gnomad ASJ

AF:

0.0231

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0609

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0321

Gnomad OTH

AF:

0.0287

GnomAD3 exomes

AF:

0.0228

AC:

5347

AN:

234774

Hom.:

108

AF XY:

0.0232

AC XY:

3007

AN XY:

129556

show subpopulations

Gnomad AFR exome

AF:

0.00436

Gnomad AMR exome

AF:

0.0121

Gnomad ASJ exome

AF:

0.0257

Gnomad EAS exome

AF:

0.0000574

Gnomad SAS exome

AF:

0.00325

Gnomad FIN exome

AF:

0.0561

Gnomad NFE exome

AF:

0.0321

Gnomad OTH exome

AF:

0.0231

GnomAD4 exome

AF:

0.0280

AC:

40755

AN:

1456124

Hom.:

687

Cov.:

AF XY:

0.0272

AC XY:

19700

AN XY:

724486

show subpopulations

Gnomad4 AFR exome

AF:

0.00403

Gnomad4 AMR exome

AF:

0.0134

Gnomad4 ASJ exome

AF:

0.0248

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.00317

Gnomad4 FIN exome

AF:

0.0543

Gnomad4 NFE exome

AF:

0.0314

Gnomad4 OTH exome

AF:

0.0246

GnomAD4 genome

AF:

0.0229

AC:

3491

AN:

152214

Hom.:

Cov.:

AF XY:

0.0232

AC XY:

1727

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00484

Gnomad4 AMR

AF:

0.0192

Gnomad4 ASJ

AF:

0.0231

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00331

Gnomad4 FIN

AF:

0.0609

Gnomad4 NFE

AF:

0.0321

Gnomad4 OTH

AF:

0.0289

Alfa

AF:

0.0282

Hom.:

Bravo

AF:

0.0196

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

Hereditary angioedema type 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeMIA	-	The synonymous variant c.711C>T, located in exon 8 of the F12 gene, was detected in our cohort in 8 nC1-INH-HAE and 6 type I C1-INH-HAE patients. It has been detected in 2.275% alleles worldwide (gnomAD database) and its allele frequency is greater than that expected for FXII-HAE. The variant is reported as benign in ClinVar database in patients with FXII-HAE. Taking all the above into account and according to ACMG Guidelines (Criteria: BS1, BS2, BP5, BP6) the variant is considered benign. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Factor XII deficiency disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

5.2

DANN

Benign

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over