rs779802284
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000128.4(F11):c.1247G>A(p.Cys416Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,614,108 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
F11
NM_000128.4 missense
NM_000128.4 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 9.12
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 Pathogenic. Variant got 16 ACMG points.
PM1
?
In a domain Peptidase S1 (size 235) in uniprot entity FA11_HUMAN there are 63 pathogenic changes around while only 4 benign (94%) in NM_000128.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
?
Variant 4-186284203-G-A is Pathogenic according to our data. Variant chr4-186284203-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186284203-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F11 | NM_000128.4 | c.1247G>A | p.Cys416Tyr | missense_variant | 11/15 | ENST00000403665.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F11 | ENST00000403665.7 | c.1247G>A | p.Cys416Tyr | missense_variant | 11/15 | 1 | NM_000128.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251468Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135906
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GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19AN XY: 727246
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74358
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary factor XI deficiency disease Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 16, 2018 | The F11 c.1247G>A (p.Cys416Tyr) missense variant, also known as p.Cys398Tyr, has been reported in at least five studies in which it is found in at least 12 probands with factor XI deficiency, including in at least three in a homozygous state, in two in a compound heterozygous state, and in at least seven in a heterozygous state (Kravtsov et al. 2005; Mitchell et al. 2006; Zucker et al. 2007; Saunders et al. 2009; Kılıç et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.000089 in the Latino population of the Genome Aggregation Database. Functional studies in 293 and BHK fibroblasts demonstrated that the p.Cys416Tyr variant protein formed intracellular dimers but is poorly secreted, and demonstrates a dominant-negative effect on wildtype fXI secretion when cotransfected with wild type fXI (Kravtsov et al. 2005). Structural analysis indicated that the variant breaks the disulfide bridge between residues Cys398 and Cys414 disrupting folding of the serine protease domain of the protein (O'Connell et al. 2005; Saunders et al. 2009). Based on the evidence, the p.Cys416Tyr variant is classified as pathogenic for factor XI deficiency and has been described in cases following both autosomal dominant and recessive inheritance. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 20, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 17, 2020 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 30, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects F11 function (PMID: 15728123). 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. ClinVar contains an entry for this variant (Variation ID: 371565). This variant is also known as p.Cys398Tyr. This missense change has been observed in individual(s) with autosomal recessive FXI deficiency (PMID: 16835901, 18024374, 25074526, 28960694). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant FXI deficiency (PMID: 15728123, 19652879, 28960694); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (rs779802284, gnomAD 0.009%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 416 of the F11 protein (p.Cys416Tyr). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Gain of disorder (P = 0.0624);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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