NM_000505.4:c.756C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000505.4(F12):c.756C>T(p.Ala252Ala) 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

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.08

Publications

4 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 352998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
F12	NM_000505.4 link	c.756C>T	p.Ala252Ala	synonymous_variant	Exon 8 of 14	ENST00000253496.4	NP_000496.2	P00748Q8IZZ5
F12	XM_011534462.3 link	c.420C>T	p.Ala140Ala	synonymous_variant	Exon 5 of 11		XP_011532764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F12	ENST00000253496.4 link	c.756C>T	p.Ala252Ala	synonymous_variant	Exon 8 of 14	1	NM_000505.4	ENSP00000253496.3		P00748

Frequencies

GnomAD3 genomes

AF:

0.0198

AC:

3012

AN:

152162

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0133

AC:

2953

AN:

221280

AF XY:

0.0149

show subpopulations

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 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.:

AF XY:

0.00876

AC XY:

6316

AN XY:

721100

show subpopulations

African (AFR)

AF:

0.0544

AC:

1815

AN:

33366

American (AMR)

AF:

0.00865

AC:

372

AN:

43020

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

572

AN:

25814

East Asian (EAS)

AF:

0.000407

AC:

AN:

39342

South Asian (SAS)

AF:

0.0411

AC:

3496

AN:

85144

European-Finnish (FIN)

AF:

0.000671

AC:

AN:

50666

Middle Eastern (MID)

AF:

0.0302

AC:

174

AN:

5756

European-Non Finnish (NFE)

AF:

0.00347

AC:

3841

AN:

1107792

Other (OTH)

AF:

0.0123

AC:

735

AN:

59916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

722

1444

2165

2887

3609

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0198

AC:

3016

AN:

152280

Hom.:

Cov.:

AF XY:

0.0193

AC XY:

1435

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0528

AC:

2193

AN:

41558

American (AMR)

AF:

0.0109

AC:

167

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.0414

AC:

200

AN:

4830

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00470

AC:

320

AN:

68014

Other (OTH)

AF:

0.0218

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

148

296

443

591

739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0125

Hom.:

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary angioedema type 3

Benign:2

CeMIA

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

2.5

(source)

DANN

Benign

0.92

PhyloP100

-2.1

PromoterAI

0.059

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over