4-186288589-T-G
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_ModeratePM1PM2PP3_StrongPP5
The NM_000128.4(F11):āc.1853T>Gā(p.Ile618Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,614,002 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). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I618V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000128.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F11 | NM_000128.4 | c.1853T>G | p.Ile618Ser | missense_variant | 15/15 | ENST00000403665.7 | |
F11-AS1 | NR_033900.1 | n.905A>C | non_coding_transcript_exon_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F11 | ENST00000403665.7 | c.1853T>G | p.Ile618Ser | missense_variant | 15/15 | 1 | NM_000128.4 | P1 | |
F11-AS1 | ENST00000505103.5 | n.844A>C | non_coding_transcript_exon_variant | 3/4 | 1 | ||||
F11 | ENST00000264691.4 | c.455T>G | p.Ile152Ser | missense_variant | 3/3 | 3 | |||
F11 | ENST00000503841.1 | n.372T>G | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251404Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135866
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461862Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24AN XY: 727236
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74310
ClinVar
Submissions by phenotype
not provided Uncertain:1Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19652879, 16835901, 15953011) - |
F11-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 29, 2023 | The F11 c.1853T>G variant is predicted to result in the amino acid substitution p.Ile618Ser. This variant, also referred to as c.1896T>G (p.Ile600Ser), has previously been reported to be causative for Hemophilia C (see patient IDs 033061 and 5964 in Mitchell et al. 2006. PubMed ID: 16835901; family 12 in Hill et al. 2005. PubMed ID: 15953011). In Mitchell et al., patient 033061 was homozygous for the c.1853T>G variant and exhibited <2% normal FXI protein activity compared to patient 5946 which was heterozygous for the variant and exhibited 23% FXI activity. Acquired disease states including liver disease, may also alter FXI activity. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at