chr4-186288589-T-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_ModeratePM1PM2PP3_StrongPP5_Moderate
The NM_000128.4(F11):c.1853T>G(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 Pathogenic (★). 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
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ACMG classification
Verdict is Pathogenic. Variant got 12 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
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. - |
not provided Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at