chr5-177402460-C-T

Variant names:

• chr5-177402460-C-T
• rs199988476
• NM_000505.4:c.1681-1G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PVS1 PP5 BS1_Supporting

The NM_000505.4(F12):​c.1681-1G>A variant causes a splice acceptor, intron 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, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 7.55

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• 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: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=2}. Variant chr5-177402460-C-T is described in Lovd as [Likely_pathogenic]. Variant chr5-177402460-C-T is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000322 (49/152258) while in subpopulation NFE AF= 0.000514 (35/68040). AF 95% confidence interval is 0.000379. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F12	NM_000505.4	c.1681-1G>A		splice_acceptor_variant, intron_variant	Intron 13 of 13	ENST00000253496.4	NP_000496.2
F12	XM_011534462.3	c.1345-1G>A		splice_acceptor_variant, intron_variant	Intron 10 of 10		XP_011532764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F12	ENST00000253496.4	c.1681-1G>A		splice_acceptor_variant, intron_variant	Intron 13 of 13	1	NM_000505.4	ENSP00000253496.3

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152258 Hom.: 0 Cov.: 33

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: 93 AN: 229800 Hom.: 0 AF XY: 0.000352 AC XY: 44 AN XY: 124910

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.: 0 Cov.: 31 AF XY: 0.000350 AC XY: 253 AN XY: 721974

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: 49 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74390

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.: 0

Bravo AF: 0.000283

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000322 AC: 39

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	F12: PVS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 15, 2024	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) -

Factor XII deficiency disease Pathogenic:2

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

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	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
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

Other links and lift over

dbSNP: rs199988476; hg19: chr5-176829461;