rs768474112
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000128.4(F11):c.325G>A(p.Ala109Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000809 in 1,607,398 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
F11
NM_000128.4 missense, splice_region
NM_000128.4 missense, splice_region
Scores
1
5
3
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.84
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 14 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 4-186273177-G-A is Pathogenic according to our data. Variant chr4-186273177-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F11 | NM_000128.4 | c.325G>A | p.Ala109Thr | missense_variant, splice_region_variant | 4/15 | ENST00000403665.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F11 | ENST00000403665.7 | c.325G>A | p.Ala109Thr | missense_variant, splice_region_variant | 4/15 | 1 | NM_000128.4 | P1 | |
F11 | ENST00000492972.6 | c.325G>A | p.Ala109Thr | missense_variant, splice_region_variant | 4/5 | 2 | |||
F11 | ENST00000514715.1 | n.197G>A | splice_region_variant, non_coding_transcript_exon_variant | 1/2 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152098Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251254Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135786
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GnomAD4 exome AF: 0.00000618 AC: 9AN: 1455300Hom.: 0 Cov.: 27 AF XY: 0.00000828 AC XY: 6AN XY: 724542
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152098Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74306
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary factor XI deficiency disease Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant in c.325G>A (p.Ala109Thr) in F11 gene has been reported previously in individual(s) in homozygous state with factor XI (FXI) deficiency (Guella I et al). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. Previously, Guella I et al. reported a heterozygous p.A109T mutation in an Italian family with FXI deficiency. Heterozygosity moderately decreases the activity of FXI (VS Hançer et al). The p.Ala109Thr variant is reported with the allele frequency of 0.002123% in gnomAD database and is novel (not in any individuals) in 1000 Genomes. The amino acid Ala at position 109 is changed to a Thr changing protein sequence and it might alter its composition and physicochemical properties. This variant has been reported to the ClinVar database as conflicting - pathogenic/ likely pathogenic/ uncertain significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (Buratti E et al). Experimental studies have shown that this variant disrupts mRNA splicing (Guella I et al). The variant is predicted to be damaging by SIFT and the residue is conserved across species. The amino acid change p.Ala109Thr in F11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant the molecular diagnosis is not confirmed. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | May 31, 2014 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 26, 2022 | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 18327400). ClinVar contains an entry for this variant (Variation ID: 188810). This variant is also known as Ala91Thr. This variant has been observed in individual(s) with factor XI deficiency (PMID: 18515884, 25158988). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs768474112, gnomAD 0.006%). This sequence change affects codon 109 of the F11 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the F11 protein. This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 27, 2022 | PP1_strong, PM2, PM3, PS3 - |
Plasma factor XI deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 07, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MutationTaster
Benign
D;D;D
ClinPred
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at