rs183643295

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000505.4(F12):c.1027G>C(p.Ala343Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,602,464 control chromosomes in the GnomAD database, including 37 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 32 hom. )

Consequence

F12
NM_000505.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:9

Conservation

PhyloP100: -0.0910

Publications

8 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=0.0036440194).

BP6

Variant 5-177404082-C-G is Benign according to our data. Variant chr5-177404082-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 225352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00145 (221/152366) while in subpopulation EAS AF = 0.028 (145/5174). AF 95% confidence interval is 0.0243. There are 5 homozygotes in GnomAd4. There are 129 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F12	NM_000505.4 link	c.1027G>C	p.Ala343Pro	missense_variant	Exon 10 of 14	ENST00000253496.4	NP_000496.2	P00748Q8IZZ5
F12	XM_011534462.3 link	c.691G>C	p.Ala231Pro	missense_variant	Exon 7 of 11		XP_011532764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F12	ENST00000253496.4 link	c.1027G>C	p.Ala343Pro	missense_variant	Exon 10 of 14	1	NM_000505.4	ENSP00000253496.3		P00748

Frequencies

GnomAD3 genomes

AF:

0.00146

AC:

222

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0280

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00546

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00315

AC:

701

AN:

222724

AF XY:

0.00283

show subpopulations

Gnomad AFR exome

AF:

0.0000746

Gnomad AMR exome

AF:

0.0000298

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0347

Gnomad FIN exome

AF:

0.00489

Gnomad NFE exome

AF:

0.0000406

Gnomad OTH exome

AF:

0.000543

GnomAD4 exome

AF:

0.00144

AC:

2093

AN:

1450098

Hom.:

Cov.:

AF XY:

0.00143

AC XY:

1030

AN XY:

721632

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33446

American (AMR)

AF:

0.0000226

AC:

AN:

44320

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26008

East Asian (EAS)

AF:

0.0433

AC:

1712

AN:

39582

South Asian (SAS)

AF:

0.000501

AC:

AN:

85812

European-Finnish (FIN)

AF:

0.00411

AC:

182

AN:

44336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000369

AC:

AN:

1110752

Other (OTH)

AF:

0.00185

AC:

111

AN:

60090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

144

288

431

575

719

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00145

AC:

221

AN:

152366

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

129

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41592

American (AMR)

AF:

0.000196

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0280

AC:

145

AN:

5174

South Asian (SAS)

AF:

0.000829

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00546

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000169

Hom.:

Bravo

AF:

0.00130

ExAC

AF:

0.00281

AC:

336

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Factor XII deficiency disease

Pathogenic:1Benign:3

Oct 29, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:reference population

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

F12: BP4, BS1, BS2 -

not specified

Benign:1

Mar 29, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ala343Pro variant in F12 is classified as likely benign because it has been identified in 4.1% (1857/44756) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). ACMG/AMP Criteria applied: BS1. -

F12-related disorder

Benign:1

Sep 05, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.35

CADD

Benign

3.2

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.060

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.33

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.0

PhyloP100

-0.091

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.45

REVEL

Benign

0.20

Sift

Uncertain

0.027

Sift4G

Benign

0.14

Polyphen

0.0

Vest4

0.12

MVP

0.70

MPC

1.1

ClinPred

0.011

GERP RS

-4.8

PromoterAI

0.0078

Neutral

(source)

Varity_R

0.093

gMVP

0.50

Mutation Taster

=92/8

disease causing (ClinVar)

(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