rs17876032

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000505.4(F12):c.1251-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 1,600,484 control chromosomes in the GnomAD database, including 296,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 21090 hom., cov: 33)

Exomes 𝑓: 0.60 ( 275054 hom. )

Consequence

F12
NM_000505.4 intron

Scores

Splicing: ADA: 0.00001529

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.732

Publications

17 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 5-177403626-G-A is Benign according to our data. Variant chr5-177403626-G-A is described in ClinVar as Benign. ClinVar VariationId is 256309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F12	NM_000505.4 link	c.1251-9C>T		intron_variant	Intron 10 of 13	ENST00000253496.4	NP_000496.2	P00748Q8IZZ5
F12	XM_011534462.3 link	c.915-9C>T		intron_variant	Intron 7 of 10		XP_011532764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F12	ENST00000253496.4 link	c.1251-9C>T		intron_variant	Intron 10 of 13	1	NM_000505.4	ENSP00000253496.3		P00748

Frequencies

GnomAD3 genomes

AF:

0.472

AC:

71788

AN:

152016

Hom.:

21097

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.650

Gnomad AMR

AF:

0.494

Gnomad ASJ

AF:

0.676

Gnomad EAS

AF:

0.225

Gnomad SAS

AF:

0.382

Gnomad FIN

AF:

0.690

Gnomad MID

AF:

0.642

Gnomad NFE

AF:

0.647

Gnomad OTH

AF:

0.529

GnomAD2 exomes

AF:

0.517

AC:

120945

AN:

233808

AF XY:

0.531

show subpopulations

Gnomad AFR exome

AF:

0.129

Gnomad AMR exome

AF:

0.365

Gnomad ASJ exome

AF:

0.678

Gnomad EAS exome

AF:

0.225

Gnomad FIN exome

AF:

0.687

Gnomad NFE exome

AF:

0.656

Gnomad OTH exome

AF:

0.578

GnomAD4 exome

AF:

0.603

AC:

873388

AN:

1448350

Hom.:

275054

Cov.:

AF XY:

0.600

AC XY:

432178

AN XY:

720510

show subpopulations

African (AFR)

AF:

0.117

AC:

3897

AN:

33332

American (AMR)

AF:

0.382

AC:

16968

AN:

44408

Ashkenazi Jewish (ASJ)

AF:

0.677

AC:

17643

AN:

26074

East Asian (EAS)

AF:

0.269

AC:

10619

AN:

39518

South Asian (SAS)

AF:

0.409

AC:

35150

AN:

85960

European-Finnish (FIN)

AF:

0.679

AC:

30373

AN:

44748

Middle Eastern (MID)

AF:

0.629

AC:

2727

AN:

4334

European-Non Finnish (NFE)

AF:

0.650

AC:

721918

AN:

1110078

Other (OTH)

AF:

0.569

AC:

34093

AN:

59898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

22102

44204

66305

88407

110509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18512

37024

55536

74048

92560

<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:

0.472

AC:

71781

AN:

152134

Hom.:

21090

Cov.:

AF XY:

0.472

AC XY:

35084

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.138

AC:

5715

AN:

41542

American (AMR)

AF:

0.493

AC:

7536

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.676

AC:

2345

AN:

3470

East Asian (EAS)

AF:

0.224

AC:

1156

AN:

5154

South Asian (SAS)

AF:

0.384

AC:

1850

AN:

4822

European-Finnish (FIN)

AF:

0.690

AC:

7311

AN:

10598

Middle Eastern (MID)

AF:

0.626

AC:

184

AN:

294

European-Non Finnish (NFE)

AF:

0.647

AC:

43984

AN:

67946

Other (OTH)

AF:

0.527

AC:

1112

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1612

3223

4835

6446

8058

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

618

1236

1854

2472

3090

<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:

0.595

Hom.:

51878

Bravo

AF:

0.444

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary angioedema type 3

Benign:2

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary angioneurotic edema

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Factor XII deficiency disease

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nephrolithiasis/osteoporosis, hypophosphatemic

Benign:1

Jun 14, 2016

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

-0.77

CADD

Benign

8.2

(source)

DANN

Benign

0.82

PhyloP100

0.73

PromoterAI

-0.040

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000015

dbscSNV1_RF

Benign

0.0040

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

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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