4-186274193-G-T

Position:

• chr4-186274193-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000128.4(F11):​c.403G>T​(p.Glu135*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000516 in 1,614,080 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00063 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (6 hom.)
• Consequence: F11 NM_000128.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:26
• Conservation: PhyloP100: 1.79

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]

F11 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 4-186274193-G-T is Pathogenic according to our data. Variant chr4-186274193-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 11891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186274193-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F11	NM_000128.4	c.403G>T	p.Glu135*	stop_gained	5/15	ENST00000403665.7	NP_000119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F11	ENST00000403665.7	c.403G>T	p.Glu135*	stop_gained	5/15	1	NM_000128.4	ENSP00000384957.2
F11	ENST00000492972.6	c.403G>T	p.Glu135*	stop_gained	5/5	2		ENSP00000424479.1
F11	ENST00000514715.1	n.275G>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152188 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000927 AC: 233 AN: 251292 Hom.: 3 AF XY: 0.000957 AC XY: 130 AN XY: 135802

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000504 AC: 737 AN: 1461892 Hom.: 6 Cov.: 31 AF XY: 0.000513 AC XY: 373 AN XY: 727246

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0177

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000145

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.000631 AC: 96 AN: 152188 Hom.: 1 Cov.: 33 AF XY: 0.000632 AC XY: 47 AN XY: 74338

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.0185

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00108 Hom.: 1

Bravo AF: 0.000567

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000782 AC: 95

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000474

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor XI deficiency disease Pathogenic:16

Pathogenic, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Sep 12, 2022	This sequence variant is a single nucleotide substitution (G>T) at coding position 403 of the F11 gene that results in the generation of an early termition codon at residue 135 of the F11 protein and has also been referred to as E117X in the published literature. This variant is predicted to generate a non-functiol allele through either the expression of a truncated protein or a loss of F11 expression due to nonsense mediated decay. This is a previously reported (ClinVar), well-known founder variant in the Ashkezi Jewish population (PMID: 23332144) that has been observed in the literature in many individuals with factor 11 deficiency (PMID: 16835901, 29178608, 29138690, 32935436). This variant is present in the gnomAD control population database (244 of 282694 alleles or 0.08%). Functiol studies have confirmed that this variant results in a loss of F11 protein expression (PMID: 15026311). Given the evidence, we consider this variant to be pathogenic. ACMG Criteria: PP5, PS3, PS4, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 26, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 18, 1991	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	The c.403G>T (p.Glu135Ter) stop-gained variant is a founder variant in the Ashkenazi Jewish population predicted to result in premature termination of the protein. The p.Glu135Ter variant has been reported in three studies and is found in a total of 28 factor XI deficiency patients including seven homozygotes, eight compound heterozygotes, and 13 heterozygotes (Asakai et al. 1989; Bolton-Maggs et al. 2004; Mitchell et al. 2006). Control data are unavailable for this variant, which is reported at a frequency of 0.00128 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Based on the potential impact of stop-gained variants and the evidence from the literature, the p.Glu135Ter variant is classified as pathogenic for factor XI deficiency. -
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	Johns Hopkins Genomics, Johns Hopkins University	Aug 04, 2022	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000128.3:c.403G>T in the F11 gene has an allele frequency of 0.017 in Ashkenazi Jewish subpopulation in the gnomAD database. The c.403G>T (p.Glu135Ter) stop-gained variant is a founder variant in the Ashkenazi Jewish population predicted to result in premature termination of the protein. The p.Glu135Ter variant has been reported in factor XI deficiency patients, compound heterozygotes with p.Q251X and p.F301L (also known as F283L) (PMID: 15140127; 16835901). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PVS1; PM3; PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with factor XI deficiency. Dominant negative missense tend to have dominant inheritance patterns (PMID:15026311), while loss of function variants are generally recessive, though symptomatic carriers have been reported (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Recessive cases are more severe than heterozygous carriers, who may be asymptomatic despite having FXI deficiency (PMID:18446632). (I) 0115 - Variants in this gene are known to have variable expressivity. There is a high degree of variable expression, where intrafamilial variation has been reported (PMID: 32118380). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD (v2) >=0.01 and <0.03 (238 heterozygotes, 3 homozygotes). (I) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. More than 10 other NMD-predicted variants have previously been reported as pathogenic in patients with factor XI deficiency (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in multiple patients with factor XI deficiency, and is considered to be a founder variant in the Ashkenazi Jewish population. Homozygous and compound heterozygous patients have severe disease, whilst heterozygous carriers have partial FX1 deficiency (ClinVar, PMID: 29178608). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 05, 2017	This c.403G>T (p.Glu135*) variant in the F11 gene was first reported in 5 compound heterozygous patients with F11 deficiency [reported as p.Glu117*, Type II mutation, in PMID 2813350]. The patients had none to moderate bleeding symptoms. This variant was also reported in 3 homozygous and 3 compound heterozygous patients of Jewish descent with F11 deficiency [PMID 15140127]. This c.403G>T variant encodes for a nonsense codon in exon 5 and creates a stop codon at amino acid position 135 of the F11 protein. This variant has been detected in 95 heterozygous and one homozygous individuals in the ExAC population database (http://exac.broadinstitute.org/variant/4-187195347-G-T). This variant is thus classified as pathogenic. <BR>Apparent homozygosity of this variant may be caused by the presence of the mutant allele on both alleles of this individual, or the presence of a mutant allele on one allele and an exonic deletion on the opposite allele. Copy number variant (CNV) analysis or segregation analysis is necessary to assess the apparent homozygosity status of this variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 31, 2020	The p.Glu135X (also known as p.Glu117X) variant in F11 has been reported in in the homozygous or compound heterozygous state in >40 individuals with factor XI deficiency and is a founder mutation in the Ashkenazi Jewish population (Asakai 1991, Bolton-Maggs 2004, Mitchell 2006). This variant has also been reported in ClinVar (Variation ID 11891) and has been identified in 1.7% (177/10364) of Ashkenazi Jewish chromosomes by gnomAD, including 3 homozygotes (http://gnomad.broadinstitute.org). However, this frequency is consistent with a recessive carrier frequency for a known founder variant. Functional studies support an impact on protein function (Asakai 1991). This nonsense variant leads to a premature termination codon at position 135, which is predicted to lead to a truncated or absent protein. Loss of function of the F11 gene is an established disease mechanism in autosomal recessive factor XI deficiency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive factor XI deficiency. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PP1, PS3_Supporting. -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	F11: PVS1, PM2, PM3, PS4:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Glu135*) in the F11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in F11 are known to be pathogenic (PMID: 23929304). This variant is present in population databases (rs121965063, gnomAD 1.8%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with Factor XI deficiency (PMID: 2813350, 15026311). This variant is also known as p.Glu117Stop. ClinVar contains an entry for this variant (Variation ID: 11891). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 06, 2024	PP5, PM3, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2024	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate that cells transfected with a vector containing the E135X variant do not generate protein (PMID: 15026311); This variant is associated with the following publications: (PMID: 25333069, 22975760, 27723456, 15140127, 30431218, 29467123, 31064749, 33527515, 30712878, 29138690, 26558335, 16835901, 29178608, 31364091, 31447099, 31624327, 32935436, 31589614, 32581362, 31345219, 2813350, 15026311, 37647632, 36964972) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2024

The c.403G>T (p.E135*) alteration, located in exon 5 (coding exon 4) of the F11 gene, consists of a G to T substitution at nucleotide position 403. This changes the amino acid from a glutamic acid (E) to a stop codon at amino acid position 135. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.086% (244/282694) total alleles studied. The highest observed frequency was 1.708% (177/10364) of Ashkenazi Jewish alleles. This alteration, previously reported as p.E117* in the literature, is common in Ashkenazi Jewish patients with factor XI deficiency, accounting for approximately 49% of disease alleles (Asakai, 1991). Additionally, this variant has been reported as heterozygous and homozygous in individuals with a personal and/or family history of a factor XI deficiency, as well as in asymptomatic individuals (Bolton-Maggs, 2004; Mitchell, 2006; Kawankar, 2016; Tiscia, 2017). Based on the available evidence, this alteration is classified as pathogenic. -

Thrombocytopenia;C1458140:Abnormal bleeding Pathogenic:1

Pathogenic, no assertion criteria provided

research

Birmingham Platelet Group; University of Birmingham

May 01, 2020

- -

F11-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2024

The F11 c.403G>T variant is predicted to result in premature protein termination (p.Glu135*). This variant, referred to as Type II Mutation and p.Glu117* using legacy nomenclature, is found frequently in Ashkenazi Jewish populations and has been reported previously to be causative for Hemophilia C (Asakai et al. 1991. PubMed ID: 2052060; Asakai et al. 1989. PubMed ID: 2813350; Kravtsov et al. 2004. PubMed ID: 15026311). Factor XI deficiency is primarily an autosomal recessive disorder. Clinical presentation varies from asymptomatic to mild bleeding in patients heterozygous for the c.403G>T (p.Glu135*) variant (Gomez and Bolton-Maggs. 2008. PubMed ID: 18312365). Nonsense variants in F11 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Plasma factor XI deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.87	D
Vest4		0.90
GERP RS		4.9

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: rs121965063; hg19: chr4-187195347;