rs281875275
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_000128.4(F11):c.1693G>A(p.Glu565Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
F11
NM_000128.4 missense
NM_000128.4 missense
Scores
3
6
10
Clinical Significance
Conservation
PhyloP100: 3.87
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a disulfide_bond (size 67) in uniprot entity FA11_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000128.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.874
PP5
?
Variant 4-186287800-G-A is Pathogenic according to our data. Variant chr4-186287800-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68186.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2, not_provided=1}. Variant chr4-186287800-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F11 | NM_000128.4 | c.1693G>A | p.Glu565Lys | missense_variant | 14/15 | ENST00000403665.7 | |
F11-AS1 | NR_033900.1 | n.1066+628C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F11 | ENST00000403665.7 | c.1693G>A | p.Glu565Lys | missense_variant | 14/15 | 1 | NM_000128.4 | P1 | |
F11-AS1 | ENST00000505103.5 | n.1005+628C>T | intron_variant, non_coding_transcript_variant | 1 | |||||
F11 | ENST00000264691.4 | c.295G>A | p.Glu99Lys | missense_variant | 2/3 | 3 | |||
F11 | ENST00000503841.1 | n.212G>A | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152096Hom.: 0 Cov.: 30
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461010Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726852
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary factor XI deficiency disease Pathogenic:2
Likely pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | May 24, 2014 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 27, 2023 | Variant summary: F11 c.1693G>A (p.Glu565Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. One study reported that this variant causes skipping of exon 14 however the results as presented do not allow a conclusive determination supporting this conclusion (Zucker_20011). The variant was absent in 251488 control chromosomes. c.1693G>A has been reported in the literature as a non-informative genotype (second allele not specified), a homozygous genotype (one report) and as a presumed compound heterozygous genotype (one report) in individuals affected with features of factor XI deficiency disease or in settings of multigene panel testing for coagulation disorders (example, Hill_2005, Qulin_2009, Karimi_2009, Zucker_2011, Rimoldi_2018, Downes_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31064749, 15953011, 18758779, 20523169, 29178608, 21718436). One group has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
not provided Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.
REVEL
Pathogenic
Sift
Benign
T;.
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MutPred
Gain of MoRF binding (P = 0.0054);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at