chr4-186287720-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000128.4(F11):c.1613C>T(p.Pro538Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000194 in 1,612,918 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 0.000092 ( 0 hom., cov: 30)
Exomes 𝑓: 0.00020 ( 0 hom. )
Consequence
F11
NM_000128.4 missense
NM_000128.4 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 7.09
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 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, 0.945
PP5
?
Variant 4-186287720-C-T is Pathogenic according to our data. Variant chr4-186287720-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186287720-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F11 | NM_000128.4 | c.1613C>T | p.Pro538Leu | missense_variant | 14/15 | ENST00000403665.7 | |
F11-AS1 | NR_033900.1 | n.1066+708G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F11 | ENST00000403665.7 | c.1613C>T | p.Pro538Leu | missense_variant | 14/15 | 1 | NM_000128.4 | P1 | |
F11-AS1 | ENST00000505103.5 | n.1005+708G>A | intron_variant, non_coding_transcript_variant | 1 | |||||
F11 | ENST00000264691.4 | c.215C>T | p.Pro72Leu | missense_variant | 2/3 | 3 | |||
F11 | ENST00000503841.1 | n.132C>T | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000924 AC: 14AN: 151542Hom.: 0 Cov.: 30
GnomAD3 genomes
?
AF:
AC:
14
AN:
151542
Hom.:
Cov.:
30
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000875 AC: 22AN: 251442Hom.: 0 AF XY: 0.0000883 AC XY: 12AN XY: 135892
GnomAD3 exomes
AF:
AC:
22
AN:
251442
Hom.:
AF XY:
AC XY:
12
AN XY:
135892
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000205 AC: 299AN: 1461376Hom.: 0 Cov.: 31 AF XY: 0.000206 AC XY: 150AN XY: 727016
GnomAD4 exome
AF:
AC:
299
AN:
1461376
Hom.:
Cov.:
31
AF XY:
AC XY:
150
AN XY:
727016
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000924 AC: 14AN: 151542Hom.: 0 Cov.: 30 AF XY: 0.0000947 AC XY: 7AN XY: 73948
GnomAD4 genome
?
AF:
AC:
14
AN:
151542
Hom.:
Cov.:
30
AF XY:
AC XY:
7
AN XY:
73948
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
1
ExAC
?
AF:
AC:
9
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary factor XI deficiency disease Pathogenic:3
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 | Jan 26, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Uncertain
D;D
Polyphen
B;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at