rs118204457

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_000505.4(F12):c.983C>A(p.Thr328Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000687 in 1,602,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T328R) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

F12
NM_000505.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.61

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 made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a glycosylation_site O-linked (GalNAc...) threonine (size 0) in uniprot entity FA12_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000505.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-177404231-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1170.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.898

PP5

Variant 5-177404231-G-T is Pathogenic according to our data. Variant chr5-177404231-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177404231-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F12	NM_000505.4 linkuse as main transcript	c.983C>A	p.Thr328Lys	missense_variant	9/14	ENST00000253496.4
F12	XM_011534462.3 linkuse as main transcript	c.647C>A	p.Thr216Lys	missense_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F12	ENST00000253496.4 linkuse as main transcript	c.983C>A	p.Thr328Lys	missense_variant	9/14	1	NM_000505.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000427

AC:

AN:

234142

Hom.:

AF XY:

0.00000782

AC XY:

AN XY:

127922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000297

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000621

AC:

AN:

1449748

Hom.:

Cov.:

AF XY:

0.00000556

AC XY:

AN XY:

719534

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000543

Gnomad4 OTH exome

AF:

0.0000503

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000829

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2022	Published functional studies demonstrate a damaging effect resulting in loss of glycosylation and increased microvascular leakage upon contact (Bjorkqvist et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23849223, 22920075, 21631522, 19474702, 25744496, 25790805, 25134986, 25816745, 26392288, 17186468, 27130860, 27788882, 30591525, 29128335, 30131260, 29885370, 34426522, 31589614, 26193639, 16638441) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 328 of the F12 protein (p.Thr328Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal dominant hereditary angioedema (PMID: 16638441, 22920075). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1032C>A (p.T309K). ClinVar contains an entry for this variant (Variation ID: 1169). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt F12 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects F12 function (PMID: 27130860). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 24, 2022	PP1, PM1, PM5, PS3, PS4_moderate -

Hereditary angioedema type 3

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeMIA	-	The c.983C>A (p.Thr328Lys) variant, located in exon 7 of the F12 gene, has been previously reported in the literature in association with FXII-HAE (Dewald 2006, Cichon 2006, Martin 2007, Duan 2009, Picone 2010, Mor eno 2015, Firinu 2015). It was detected by our laboratory in three patients with HAE-nC1-INH, belonging to two unrelated Spanish families. These patients demonstrate features indicative of FXII-HAE in that attacks were appeared either during gestational periods or after the administration of estrogens. Bioinformatic analysis by SIFT and PolyPhen2 algorithms predicted this mutation as tolerated and possibly damaging, respectively. It has been detected in 0.0004271% alleles worldwide (gnomAD database). The variant is reported as pathogenic in ClinVar database in patients with FXII-HAE. Taking all the above into account and according to ACMG Guidelines (Criteria:PS3, PS4, PM1, PM5, PP1) the variant is considered pathogenic. -

Factor XII deficiency disease;C1857728:Hereditary angioedema type 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hereditary angioneurotic edema

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 17, 2015

The p.Thr328Lys variant in F12 has been reported in at least 18 individuals with hereditary angioedema type 3 (HAE 3), and segregated with disease in >35 affect ed relatives (Dewald 2006, Cichon 2006, Martin 2007, Duan 2009, Picone 2010, Mor eno 2015, Firinu 2015). However, many apparently unaffected family members were also found to carry this variant, which has been partially attributed to both ag e- and sex-dependent penetrance (Dewald 2006, Martin 2007). Of note, the HAE 3 p henotype appears to be estrogen-dependent and males who carry this variant were rarely affected (Dewald 2006, Martin 2007). The p.Thr328Lys variant was also ide ntified in 1/9444 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs118204456). Please note that for disease s with clinical variability or reduced penetrance, pathogenic variants may be pr esent at a low frequency in the general population. In summary, this variant mee ts our criteria to be classified as pathogenic for HAE 3 in an autosomal dominan t manner based upon segregation studies and low frequency in controls. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

Cadd

Benign

Dann

Benign

0.97

DEOGEN2

Benign

0.083

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.39

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.90

MetaSVM

Benign

-0.31

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.51

Sift

Benign

0.032

Sift4G

Benign

0.28

Polyphen

0.91

Vest4

0.55

MutPred

0.82

Gain of methylation at T328 (P = 0.0011);

MVP

0.95

MPC

1.8

ClinPred

0.41

GERP RS

4.1

Varity_R

0.14

gMVP

0.74

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over