NM_000505.4:c.1681-1G>A

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 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:2
• Conservation: PhyloP100: 7.55
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• hereditary angioedema type 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Genomics England PanelApp, Orphanet
• congenital factor XII deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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 VariationId is 1166.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000505.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F12	NM_000505.4	MANE Select	c.1681-1G>A		splice_acceptor intron	N/A	NP_000496.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F12	ENST00000253496.4	TSL:1 MANE Select	c.1681-1G>A		splice_acceptor intron	N/A	ENSP00000253496.3
	F12	ENST00000696195.1		n.4509G>A		non_coding_transcript_exon	Exon 12 of 12
	F12	ENST00000696201.1		c.1570-1G>A		splice_acceptor intron	N/A	ENSP00000512482.1

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

GnomAD2 exomes AF: 0.000405 AC: 93 AN: 229800 AF XY: 0.000352

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 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

African (AFR) AF: 0.0000302 AC: 1 AN: 33160

American (AMR) AF: 0.0000689 AC: 3 AN: 43556

Ashkenazi Jewish (ASJ) AF: 0.00493 AC: 128 AN: 25968

East Asian (EAS) AF: 0.00 AC: 0 AN: 38926

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84956

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000305 AC: 338 AN: 1107952

Other (OTH) AF: 0.000417 AC: 25 AN: 59992

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74390

African (AFR) AF: 0.00 AC: 0 AN: 41478

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000514 AC: 35 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000556 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:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

F12: PVS1:Strong, PM2:Supporting, PM3:Supporting, PS4:Supporting

Sep 15, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 37647632)

Jun 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Factor XII deficiency disease Pathogenic:2

Mar 18, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

F12-related disorder Pathogenic:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Hereditary angioedema type 3 Uncertain:1

Apr 05, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.6
GERP RS		4.4
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199988476; hg19: chr5-176829461;