4-186288460-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.1724C>T(p.Ser575Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,912 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S575S) has been classified as Likely benign.
Frequency
Consequence
NM_000128.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F11 | NM_000128.4 | c.1724C>T | p.Ser575Leu | missense_variant | 15/15 | ENST00000403665.7 | |
F11-AS1 | NR_033900.1 | n.1034G>A | non_coding_transcript_exon_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F11 | ENST00000403665.7 | c.1724C>T | p.Ser575Leu | missense_variant | 15/15 | 1 | NM_000128.4 | P1 | |
F11-AS1 | ENST00000505103.5 | n.973G>A | non_coding_transcript_exon_variant | 3/4 | 1 | ||||
F11 | ENST00000264691.4 | c.326C>T | p.Ser109Leu | missense_variant | 3/3 | 3 | |||
F11 | ENST00000503841.1 | n.243C>T | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152122Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461790Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727192
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152122Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74310
ClinVar
Submissions by phenotype
Hereditary factor XI deficiency disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Mar 30, 2016 | The c.1724C>T (p.Ser575Leu) missense variant in the F11 gene has been previously reported in three unrelated individuals affected with CRM+ Factor XI deficiency. Consistent with the CRM+ type Factor XI deficiency, these individuals had reduced coagulation activity but normal antigen levels (FXI:Ag = 60-86 UI/dL) indicating there was normal level of protein present in the plasma, but reduced enzyme function (Guéguen et al., 2012). The individual who was homozygous for this variant had lower coagulation activity (FXI C:1 UI/dL) compared with the two individuals who were heterozygous for this variant (FXI C: 28 UI/dL and 38 UI/dL respectively; normal range 70-15 IU/dL). The c.1724C>T (p.Ser575Leu) variant is located in the active site of the FXI protein, which would be predicted to inhibit the serine protease function of the protein. This variant is absent from the population databases (Exome Sequencing Project; 1000 Genomes; ExAC). Multiple in silico algorithms predict a deleterious effect (GERP = 5.05; CADD = 16.48; PolyPhen = 1.0; SIFT = 0). Therefore, this collective evidence supports the classification of the c.1724C>T (p.Ser575Leu) as a Likely pathogenic variant for Factor XI Deficiency. - |
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