rs121965070

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP2PP5

The NM_000128.4(F11):c.809A>T(p.Lys270Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000544 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00055 ( 0 hom. )

Consequence

F11
NM_000128.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:3O:1

Conservation

PhyloP100: -0.442

Publications

5 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

congenital factor XI deficiency
Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

F11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 47 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 0.019886 (below the threshold of 3.09). Trascript score misZ: 0.83889 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital factor XI deficiency.

PP5

Variant 4-186280065-A-T is Pathogenic according to our data. Variant chr4-186280065-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11902.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F11	NM_000128.4 link	c.809A>T	p.Lys270Ile	missense_variant	Exon 8 of 15	ENST00000403665.7	NP_000119.1	P03951-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F11	ENST00000403665.7 link	c.809A>T	p.Lys270Ile	missense_variant	Exon 8 of 15	1	NM_000128.4	ENSP00000384957.2		P03951-1
F11	ENST00000452239.1 link	c.254A>T	p.Lys85Ile	missense_variant	Exon 3 of 6	5		ENSP00000397401.1		H0Y596

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000497

AC:

125

AN:

251364

AF XY:

0.000478

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.000818

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000547

AC:

799

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000529

AC XY:

385

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00133

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000633

AC:

704

AN:

1111964

Other (OTH)

AF:

0.000281

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

133

178

222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000519

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000794

AC:

AN:

68034

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000864

Hom.:

Bravo

AF:

0.000427

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000445

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary factor XI deficiency disease

Pathogenic:3Uncertain:2

Jun 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Oct 01, 2021

Myriad Genetics, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_000128.3(F11):c.809A>T(K270I) is a missense variant classified as a variant of uncertain significance in the context of factor XI deficiency. K270I has been observed in cases with relevant disease (PMID: 15180874, 18839438, 18446632, 31064749). Functional assessments of this variant are available in the literature (PMID: 15180874). K270I has been observed in population frequency databases (gnomAD: FIN 0.13%). In summary, there is insufficient evidence to classify NM_000128.3(F11):c.809A>T(K270I) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Jul 23, 2022

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence variant is a single nucleotide substitution (A>T) at coding position 809 in the F11 gene which results in a lysine to isoleucine amino acid change at residue 270 in the F11-encoded factor XI protein. This is a previously reported variant (ClinVar) which has been observed in heterozygous and compound heterozygous state in individuals with coagulation disorders (PMID: 18839438, 16835901, 18446632, 31064749). This variant is present in 148/282756 alleles (0.05234%) in the gnomAD control population dataset. This variant occurs in the third of four apple domains in factor XI. Bioinformatic tools predict that this amino acid change is likely to be tolerated; furthermore, this amino acid residue is not well conserved in vertebrates. However, an in vitro functiol study demonstrated that cells expressing variant factor XI had ~66% decreased secretion in comparison to cells expressing wild-type protein (PMID: 15180874). Furthermore, multiple individuals that were heterozygous or compound heterozygous for this variant had factor XI antigen and activity levels consistent with a nearly complete loss of function (PMID: 18839438, 16835901). Based on the current data, we consider this variant to be likely pathogenic. ACMG Criteria: BP4, PM3, PS3, PS4 -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The F11 c.809A>T (p.Lys270Ile) missense variant, also known as p.Lys252Ile, has been reported in three studies and is found in a compound heterozygous state in at least four individuals with factor XI deficiency, two of whom were related, and in a heterozygous state in two family members of one of the compound heterozygotes, though phenotype information is not provided (Dai et al. 2004; Mitchell et al. 2006; Castaman et al. 2008). Control data are unavailable for this variant, which is reported at a frequency of 0.00151 in the European (Finnish) population of the Exome Aggregation Consortium. Functional studies in hamster kidney cells demonstrated that while the p.Lys270Ile variant protein was synthesized and expressed intracellularly at levels similar to wild type, secretion of the variant protein was reduced by 73% (Dai et al. 2004). Based on the evidence, the p.Lys270Ile variant is classified as likely pathogenic for factor XI deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Uncertain:1Other:1

Jun 08, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

UniProtKB/Swiss-Prot

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Uncertain

0.47

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.42

T;T

M_CAP

Benign

0.047

MetaRNN

Uncertain

0.68

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.60

N;.

PhyloP100

-0.44

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.3

N;.

REVEL

Uncertain

0.54

Sift

Benign

0.15

T;.

Sift4G

Benign

0.15

T;T

Polyphen

0.0060

B;.

Vest4

0.57

MVP

0.77

MPC

0.20

ClinPred

0.0081

GERP RS

-7.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.25

gMVP

0.71

Mutation Taster

=22/78

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over