rs137852243
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_000133.4(F9):c.682G>A(p.Val228Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000165 in 1,209,686 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V228F) has been classified as Pathogenic.
Frequency
Consequence
NM_000133.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F9 | NM_000133.4 | c.682G>A | p.Val228Ile | missense_variant | 6/8 | ENST00000218099.7 | |
F9 | NM_001313913.2 | c.568G>A | p.Val190Ile | missense_variant | 5/7 | ||
F9 | XM_005262397.5 | c.553G>A | p.Val185Ile | missense_variant | 5/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F9 | ENST00000218099.7 | c.682G>A | p.Val228Ile | missense_variant | 6/8 | 1 | NM_000133.4 | P1 | |
F9 | ENST00000394090.2 | c.568G>A | p.Val190Ile | missense_variant | 5/7 | 1 | |||
F9 | ENST00000643157.1 | n.1349G>A | non_coding_transcript_exon_variant | 4/7 |
Frequencies
GnomAD3 genomes ? AF: 0.00000896 AC: 1AN: 111558Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 33734
GnomAD4 exome AF: 9.11e-7 AC: 1AN: 1098128Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1AN XY: 363486
GnomAD4 genome ? AF: 0.00000896 AC: 1AN: 111558Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 33734
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 24, 2023 | Variant summary: F9 c.682G>A (p.Val228Ile) results in a conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. This alters a highly conserved residue in which two other missense variants (p.V228L, p.V228F) have been found in association with Haemophilia B (HGMD). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183450 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.682G>A in individuals affected with Factor IX Deficiency (Hemophilia B) and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at