rs41309752

Positions:

• chr5-177404543-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000505.4(F12):​c.756C>T​(p.Ala252=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00878 in 1,603,096 control chromosomes in the GnomAD database, including 261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (69 hom., cov: 33)
  • Exomes 𝑓: 0.0076 (192 hom.)
• Consequence: F12 NM_000505.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.08

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]

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 5-177404543-G-A is Benign according to our data. Variant chr5-177404543-G-A is described in ClinVar as [Benign]. Clinvar id is 352998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177404543-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F12	NM_000505.4	c.756C>T	p.Ala252=	synonymous_variant	8/14	ENST00000253496.4
F12	XM_011534462.3	c.420C>T	p.Ala140=	synonymous_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F12	ENST00000253496.4	c.756C>T	p.Ala252=	synonymous_variant	8/14	1	NM_000505.4	P1

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 3012 AN: 152162 Hom.: 69 Cov.: 33

Gnomad AFR AF: 0.0527

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0422

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.00470

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.0133 AC: 2953 AN: 221280 Hom.: 60 AF XY: 0.0149 AC XY: 1815 AN XY: 122038

Gnomad AFR exome AF: 0.0565

Gnomad AMR exome AF: 0.00775

Gnomad ASJ exome AF: 0.0229

Gnomad EAS exome AF: 0.000244

Gnomad SAS exome AF: 0.0416

Gnomad FIN exome AF: 0.000595

Gnomad NFE exome AF: 0.00491

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.00762 AC: 11055 AN: 1450816 Hom.: 192 Cov.: 37 AF XY: 0.00876 AC XY: 6316 AN XY: 721100

Gnomad4 AFR exome AF: 0.0544

Gnomad4 AMR exome AF: 0.00865

Gnomad4 ASJ exome AF: 0.0222

Gnomad4 EAS exome AF: 0.000407

Gnomad4 SAS exome AF: 0.0411

Gnomad4 FIN exome AF: 0.000671

Gnomad4 NFE exome AF: 0.00347

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.0198 AC: 3016 AN: 152280 Hom.: 69 Cov.: 33 AF XY: 0.0193 AC XY: 1435 AN XY: 74472

Gnomad4 AFR AF: 0.0528

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0414

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00470

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0125 Hom.: 13

Bravo AF: 0.0212

Asia WGS AF: 0.0320 AC: 113 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Hereditary angioedema type 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	CeMIA	-	The synonymous variant c.756C>T, located in exon 8 of the F12 gene was detected in our cohort in 4 nC1-INH-HAE and 5 type I C1-INH-HAE patients. It has been detected in 1.389% 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	-0.70
CADD	Benign	2.5
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41309752; hg19: chr5-176831544;