rs756908183
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_000128.4(F11):c.400C>T(p.Gln134Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,614,042 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). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000128.4 stop_gained
Scores
Clinical Significance
Conservation
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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.400C>T | p.Gln134Ter | stop_gained | 5/15 | ENST00000403665.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F11 | ENST00000403665.7 | c.400C>T | p.Gln134Ter | stop_gained | 5/15 | 1 | NM_000128.4 | P1 | |
F11 | ENST00000492972.6 | c.400C>T | p.Gln134Ter | stop_gained | 5/5 | 2 | |||
F11 | ENST00000514715.1 | n.272C>T | non_coding_transcript_exon_variant | 2/2 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152156Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251280Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135790
GnomAD4 exome AF: 0.0000349 AC: 51AN: 1461886Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 727240
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152156Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74320
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 29, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188913). This variant is also known as Gln116X. This premature translational stop signal has been observed in individual(s) with autosomal recessive severe factor XI deficiency (PMID: 16519703, 18515884). This variant is present in population databases (rs756908183, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Gln134*) in the F11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in F11 are known to be pathogenic (PMID: 23929304). - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 28, 2021 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Identified in the heterozygous state in an individual with a factor XI antigen level of 43%, but who did not have spontaneous bleeding or bleeding with hemostatic challenge (Dossenbach-Glaninger et al., 2006); Identified in an individual who had minor bleeding after surgery and a factor XI antigen level of 4%, who also harbored a second variant in F11 (Castaman et al., 2008); Also known as Q116X due to alternate nomenclature; This variant is associated with the following publications: (PMID: 10593931, 18515884, 16519703) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 26, 2016 | - - |
Hereditary factor XI deficiency disease Pathogenic:3Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 29, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Aug 06, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 06, 2018 | The F11 c.400C>T (p.Gln134Ter) variant, also known as p.Gln116Ter, is a stop-gained variant that is predicted to result in a premature termination of the protein. Dossenbach-Glaninger et al. (2006) identified the p.Gln134Ter variant in a heterozygous state in an Austrian probands with factor XI deficiency. The proband had approximately half the normal level of factor XI. Control data are unavailable for this variant, which is reported at a frequency of 0.000063 in the European (non-Finnish) population of the Genome Aggregation Database. Due to the potential impact of stop-gained variants and the limited evidence from the literature, the p.Gln134Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for factor XI deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Abnormal bleeding Pathogenic:1
Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Plasma factor XI deficiency Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at