5-177404825-C-G

Variant names:

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.619G>C(p.Ala207Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.977 in 1,607,244 control chromosomes in the GnomAD database, including 767,374 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.96 ( 70890 hom., cov: 31)

Exomes 𝑓: 0.98 ( 696484 hom. )

Consequence

F12
NM_000505.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.217

Publications

25 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 (MetaRNN=1.1377568E-6).

BP6

Variant 5-177404825-C-G is Benign according to our data. Variant chr5-177404825-C-G is described in ClinVar as Benign. ClinVar VariationId is 256310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F12	NM_000505.4 link	c.619G>C	p.Ala207Pro	missense_variant	Exon 7 of 14	ENST00000253496.4	NP_000496.2	P00748Q8IZZ5
F12	XM_011534462.3 link	c.283G>C	p.Ala95Pro	missense_variant	Exon 4 of 11		XP_011532764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F12	ENST00000253496.4 link	c.619G>C	p.Ala207Pro	missense_variant	Exon 7 of 14	1	NM_000505.4	ENSP00000253496.3		P00748

Frequencies

GnomAD3 genomes

AF:

0.964

AC:

146685

AN:

152086

Hom.:

70852

Cov.:

show subpopulations

Gnomad AFR

AF:

0.959

Gnomad AMI

AF:

0.883

Gnomad AMR

AF:

0.884

Gnomad ASJ

AF:

0.990

Gnomad EAS

AF:

0.897

Gnomad SAS

AF:

0.955

Gnomad FIN

AF:

0.989

Gnomad MID

AF:

0.987

Gnomad NFE

AF:

0.988

Gnomad OTH

AF:

0.967

GnomAD2 exomes

AF:

0.949

AC:

225306

AN:

237422

AF XY:

0.955

show subpopulations

Gnomad AFR exome

AF:

0.959

Gnomad AMR exome

AF:

0.812

Gnomad ASJ exome

AF:

0.987

Gnomad EAS exome

AF:

0.886

Gnomad FIN exome

AF:

0.989

Gnomad NFE exome

AF:

0.987

Gnomad OTH exome

AF:

0.958

GnomAD4 exome

AF:

0.978

AC:

1422839

AN:

1455040

Hom.:

696484

Cov.:

AF XY:

0.978

AC XY:

707450

AN XY:

723492

show subpopulations

African (AFR)

AF:

0.955

AC:

31816

AN:

33324

American (AMR)

AF:

0.822

AC:

36114

AN:

43924

Ashkenazi Jewish (ASJ)

AF:

0.987

AC:

25678

AN:

26026

East Asian (EAS)

AF:

0.915

AC:

36023

AN:

39384

South Asian (SAS)

AF:

0.958

AC:

81840

AN:

85444

European-Finnish (FIN)

AF:

0.989

AC:

51149

AN:

51716

Middle Eastern (MID)

AF:

0.966

AC:

5000

AN:

5174

European-Non Finnish (NFE)

AF:

0.988

AC:

1096727

AN:

1109994

Other (OTH)

AF:

0.974

AC:

58492

AN:

60054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

1820

3641

5461

7282

9102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21612

43224

64836

86448

108060

<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:

0.964

AC:

146777

AN:

152204

Hom.:

70890

Cov.:

AF XY:

0.962

AC XY:

71601

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.959

AC:

39829

AN:

41530

American (AMR)

AF:

0.883

AC:

13510

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.990

AC:

3436

AN:

3472

East Asian (EAS)

AF:

0.896

AC:

4616

AN:

5150

South Asian (SAS)

AF:

0.956

AC:

4604

AN:

4818

European-Finnish (FIN)

AF:

0.989

AC:

10495

AN:

10612

Middle Eastern (MID)

AF:

0.986

AC:

290

AN:

294

European-Non Finnish (NFE)

AF:

0.988

AC:

67161

AN:

68010

Other (OTH)

AF:

0.963

AC:

2031

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

260

519

779

1038

1298

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

912

1824

2736

3648

4560

<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:

0.981

Hom.:

23697

Bravo

AF:

0.954

TwinsUK

AF:

0.988

AC:

3663

ALSPAC

AF:

0.987

AC:

3803

ESP6500AA

AF:

0.960

AC:

4218

ESP6500EA

AF:

0.986

AC:

8470

ExAC

AF:

0.954

AC:

115051

Asia WGS

AF:

0.924

AC:

3216

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary angioedema type 3

Benign:3

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

CeMIA

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (BA1), allele frequency is greater than expected for disorder (BS1), it is observed in a healthy adult individual (BS2), it is predicted to be benign by multiple in silico algorithms (BP4), it is found in a case with an alternate molecular basis for the disease (BP5) and/or reputable source recently reports variant as benign (BP6). -

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

- -

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

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

9.3

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.24

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0064

LIST_S2

Benign

0.042

MetaRNN

Benign

0.0000011

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.82

PhyloP100

0.22

PrimateAI

Benign

0.28

PROVEAN

Benign

1.2

REVEL

Benign

0.098

Sift

Benign

0.31

Sift4G

Benign

0.45

Polyphen

0.0

Vest4

0.045

MPC

0.98

ClinPred

0.014

GERP RS

2.1

PromoterAI

0.014

Neutral

(source)

Varity_R

0.093

gMVP

0.83

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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