rs121965064

chr4-186280258-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 10P and 5B. PM1 PP5_Very_Strong BP4 BS2

The NM_000128.4(F11):c.901T>C(p.Phe301Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000604 in 1,614,068 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (8 hom.)
• Consequence: F11 NM_000128.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 5.19

Genes affected

F11 (HGNC:3529): (coagulation factor XI) This gene encodes coagulation factor XI of the blood coagulation cascade. This protein is present in plasma as a zymogen, which is a unique plasma coagulation enzyme because it exists as a homodimer consisting of two identical polypeptide chains linked by disulfide bonds. During activation of the plasma factor XI, an internal peptide bond is cleaved by factor XIIa (or XII) in each of the two chains, resulting in activated factor XIa, a serine protease composed of two heavy and two light chains held together by disulfide bonds. This activated plasma factor XI triggers the middle phase of the intrisic pathway of blood coagulation by activating factor IX. Defects in this factor lead to Rosenthal syndrome, a blood coagulation abnormality. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a disulfide_bond (size 83) in uniprot entity FA11_HUMAN there are 30 pathogenic changes around while only 2 benign (94%) in NM_000128.4
• PP5: Variant 4-186280258-T-C is Pathogenic according to our data. Variant chr4-186280258-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 11892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186280258-T-C is described in Lovd as [Likely_pathogenic]. Variant chr4-186280258-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.025343835).. Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F11	NM_000128.4	c.901T>C	p.Phe301Leu	missense_variant	9/15	ENST00000403665.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F11	ENST00000403665.7	c.901T>C	p.Phe301Leu	missense_variant	9/15	1	NM_000128.4	P1
F11	ENST00000452239.1	c.349T>C	p.Phe117Leu	missense_variant	4/6	5

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00114 AC: 287 AN: 251422 Hom.: 5 AF XY: 0.00114 AC XY: 155 AN XY: 135884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0238

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000599 AC: 875 AN: 1461878 Hom.: 8 Cov.: 33 AF XY: 0.000609 AC XY: 443 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0243

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000115

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000525 AC XY: 39 AN XY: 74354

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.00141 Hom.: 7

Bravo AF: 0.000759

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000824 AC: 100

EpiCase AF: 0.000545

EpiControl AF: 0.000771

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor XI deficiency disease Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 17, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 15, 1992	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The F11 p.F301L variant has been reported in multiple individuals with factor XI deficiency and is an Ashkenazi Jewish founder mutation, reported to account for 47% of Ashkenazi Jewish factor XI deficiency mutant alleles in one study (Asakai_1989_PMID:2813350; Asakai_1991_PMID:2052060; Mitchell_2006_PMID:16835901). The variant was identified in dbSNP (ID: rs121965064), ClinVar (classified as pathogenic by Counsyl, EGL Genetics, Illumina and Invitae, and as likely pathogenic by Fulgent Genetics) and LOVD 3.0 (classified as pathogenic and likely pathogenic). The variant was identified in control databases in 297 of 282824 chromosomes (5 homozygous) at a frequency of 0.00105 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 247 of 10368 chromosomes (freq: 0.02382), Other in 13 of 7226 chromosomes (freq: 0.001799), European (non-Finnish) in 33 of 129144 chromosomes (freq: 0.000256) and Latino in 4 of 35438 chromosomes (freq: 0.000113), but was not observed in the African, East Asian, European (Finnish), or South Asian populations. The p.Phe301 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional expression of the p.F301L mutant human factor XI protein demonstrated impaired dimerization leading reduced secretion compared to wildtype (Meijers_1992_PMID:1547342). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 14, 2018	The F11 c.901T>C (p.Phe301Leu) variant has been reported in at least four studies in seven individuals in a homozygous state, ten individuals in a compound heterozygous state, and was found in an additional 13 of 116 affected individuals of varied ethnicity in whom zygosity was not specified (Asakai et al. 1989; Asakai et al. 1991; Mitchell et al. 2006; Pike et al. 2016). All individuals had factor XI deficiency. The variant was also reported in a heterozygous state in six individuals who had factor XI activity ranging between 47% and 106%. The p.Phe301Leu variant has been found in two of 53 controls and is reported at a frequency of 0.00145 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies of transfected cells carrying the p.Phe301Leu variant showed significantly reduced expression of factor XI, but comparable clotting activity to wildtype (Meijers et al. 1992). Based on the collective evidence, the p.Phe301Leu variant is classified as pathogenic for factor XI deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000128.3:c.901T>C in the F11 gene has an allele frequency of 0.024 in Ashkenazi Jewish subpopulation in the gnomAD database. The F11 c.901T>C (p.Phe301Leu) variant, also known as F283L in literatures, has been reported in individuals with factor XI deficiency in homozygous state and compound heterozygous states with p.E135X (PMID: 26558335; 2813350; 16835901). All individuals had factor XI deficiency. Experimental studies have shown that this missense change results in reduced F11 secretion and impaired dimerization (PMID: 1547342).Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PM3_Strong; PS3; PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Jan 03, 2024	The F11 c.901T>C (p.Phe301Leu) variant, also reported as Phe283Leu when numbered from the mature protein, has been reported in the heterozygous, compound heterozygous, and homozygous state in multiple individuals with factor XI deficiency (Asakai R et al., PMID: 2813350; Asakai R et al., PMID: 2052060; Mitchell M et al., PMID: 16835901; Pike GN et al., PMID: 26558335). Individuals who are heterozygous for this variant experience partial factor XI deficiency, while individuals who are compound heterozygous or homozygous for this variant experience severe factor XI deficiency. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 2.4% in the Ashkenazi Jewish population, which is consistent with the frequency of partial factor XI deficiency in that population. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to factor XI function. In support of this prediction, studies of transfected cells carrying the p.Phe301Leu variant showed significantly reduced expression of factor XI, but comparable clotting activity to wildtype (Meijers JC et al., PMID: 1547342). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 23, 2015	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2023	Observed in the single heterozygous state in two individuals with Factor XI deficiency, one of whom was also reported to have Factor VIII deficiency (Saunders et al., 2009); Published functional studies demonstrate a damaging effect: impaired dimer formation resulting in decreased factor XI secretion (Kravtsov et al., 2004; Zucker et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9787168, 11564078, 18839438, 23332144, 16086308, 21668437, 22016685, 31064749, 19652879, 15026311, 1547342, 22975760, 25333069, 2813350, 26558335, 17384215, 22159456, 25158988, 16835901, 24982842, 19347998, 15140127, 18024374, 18515884, 29178608, 30487145, 31447099, 31980526, 34570182, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	F11: PM3:Very Strong, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 28, 2022	PP1, PP3, PP4, PP5, PM1, PM3, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 301 of the F11 protein (p.Phe301Leu). This variant is present in population databases (rs121965064, gnomAD 2.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with F11 deficiency (PMID: 2052060, 2813350, 16835901, 19652879, 23929304). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 2052060, 2813350, 16835901, 19652879, 23929304). This variant is also known as p.Phe283Leu. ClinVar contains an entry for this variant (Variation ID: 11892). 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 F11 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects F11 function (PMID: 1547342, 15026311). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 18, 2018	- -

F11-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 12, 2023

The F11 c.901T>C variant is predicted to result in the amino acid substitution p.Phe301Leu. This variant, previously reported as p.Phe283Leu, has been reported to be causative for hemophilia C in both autosomal dominant and recessive forms of the disease (Asakai et al. 1989. PubMed ID: 2813350; Kravtsov et al. 2004. PubMed ID: 15026311; Mitchell et al. 2006. PubMed ID: 16835901). This variant is reported in 2.4% of alleles in individuals of Ashkenazi Jewish descent and includes five homozygotes in gnomAD (http://gnomad.broadinstitute.org/variant/4-187201412-T-C). This variant is interpreted as pathogenic. -

Plasma factor XI deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Factor XI Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Aug 13, 2018

This c.901T>C (p.Phe301Leu) variant in the F11 gene has been reported in multiple patients with XI deficiency (PMID 2813350, 16835901, 26558335). This variant is observed in the 2.4% of Ashkenazi Jewish population and 4 times homozygous all from Ashkenazi Jewish population in the gnomAD database, while extremely rare in the other ethnic groups. In vitro assays showed that the mutant protein is secreted at a reduced level (8% of wild type) due to a defect in dimerization of the protein [PMID 1547342]. Phenylalanine at amino acid position 301 of the F11 protein is conserved in mammals. Computer-based algorithms predict this p.Phe301Leu change to be deleterious.This variant is thus classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.86	D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.025	T;T
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.1	D;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;.
Vest4		0.76
MutPred		0.85		Loss of sheet (P = 0.1398);.;
MVP		0.99
MPC		0.54
ClinPred		0.18	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.91

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

Other links and lift over

dbSNP: rs121965064; hg19: chr4-187201412;