chr5-177402460-C-T

Position:

chr5-177402460-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PP3_StrongPP5

The NM_000505.4(F12):c.1681-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00034 in 1,604,662 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

F12
NM_000505.4 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 7.55

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 5-177402460-C-T is Pathogenic according to our data. Variant chr5-177402460-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1166.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=2, Uncertain_significance=1}. Variant chr5-177402460-C-T is described in Lovd as [Likely_pathogenic]. Variant chr5-177402460-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F12	NM_000505.4 linkuse as main transcript	c.1681-1G>A		splice_acceptor_variant		ENST00000253496.4
F12	XM_011534462.3 linkuse as main transcript	c.1345-1G>A		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F12	ENST00000253496.4 linkuse as main transcript	c.1681-1G>A		splice_acceptor_variant		1	NM_000505.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000514

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000405

AC:

AN:

229800

Hom.:

AF XY:

0.000352

AC XY:

AN XY:

124910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000608

Gnomad ASJ exome

AF:

0.00435

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000471

Gnomad OTH exome

AF:

0.000176

GnomAD4 exome

AF:

0.000342

AC:

497

AN:

1452404

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

253

AN XY:

721974

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.0000689

Gnomad4 ASJ exome

AF:

0.00493

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.0000192

Gnomad4 NFE exome

AF:

0.000305

Gnomad4 OTH exome

AF:

0.000417

GnomAD4 genome

AF:

0.000322

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000514

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000684

Hom.:

Bravo

AF:

0.000283

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000322

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 03, 2023	This sequence change affects an acceptor splice site in intron 13 of the F12 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs199988476, gnomAD 0.5%). Disruption of this splice site has been observed in individual(s) with F12-related conditions (PMID: 8528215, 9354665, 25524745, 33727708). ClinVar contains an entry for this variant (Variation ID: 1166). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2024	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate the variant causes removal of the last exon, resulting in a truncated transcript and unstable protein (PMID: 8528215); Observed in the heterozygous state in an individual with recurrent angioedema and in the compound heterozygous state in individuals with Factor XII deficiency (PMID: 25524745, 9354665); This variant is associated with the following publications: (PMID: 33727708, 21920016, 24029428, 9354665, 23348723, 34426522, 25524745, 31980526, 35866546, 36685169, 8528215) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	F12: PVS1 -

Factor XII deficiency disease

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2022	- -

F12-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

The c.1681-1G>A variant has been reported in at least three studies and is found in a total of one patient in a homozygous state, four patients in a compound heterozygous state and four patients in a heterozygous state (Schloesser et al. 1995; Schloesser et al. 1997; Xu-Cai et al. 2011). The c.1681-1G>A variant was also observed in a heterozygous state in four offspring of one of the compound heterozygote patients. These individuals also exhibited reduced factor XII activity and antigen levels. Gelincik et al. (2015) identified the c.1681-1G>A variant in a heterozygous state in one patient with HAE with normal C1-INH (type 3 HAE). Factor XII levels were within normal limits in this patient. The c.1681-1G>A variant was absent from 74 control individuals and is reported at a frequency of 0.00077 in the European (non-Finnish) population of the Exome Aggregation Consortium. Transcript analysis in two compound heterozygous patients and one homozygous patient with factor XII deficiency demonstrated aberrant splicing, suggesting that the c.1681-1G>A splice acceptor variant results in detectable transcript but unstable protein (Schloesser et al. 1995). Based on the collective evidence, the c.1681-1G>A variant is classified as likely pathogenic for F12-related disorders. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

GERP RS

4.4

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.97

Position offset: -2

DS_AL_spliceai

0.98

Position offset: -1

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