chrX-139530846-T-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate
The NM_000133.4(F9):c.82T>C(p.Cys28Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C28Y) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000133.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F9 | NM_000133.4 | c.82T>C | p.Cys28Arg | missense_variant | 1/8 | ENST00000218099.7 | |
F9 | NM_001313913.2 | c.82T>C | p.Cys28Arg | missense_variant | 1/7 | ||
F9 | XM_005262397.5 | c.82T>C | p.Cys28Arg | missense_variant | 1/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F9 | ENST00000218099.7 | c.82T>C | p.Cys28Arg | missense_variant | 1/8 | 1 | NM_000133.4 | P1 | |
F9 | ENST00000394090.2 | c.82T>C | p.Cys28Arg | missense_variant | 1/7 | 1 | |||
F9 | ENST00000479617.2 | n.89T>C | non_coding_transcript_exon_variant | 1/4 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome Cov.: 28
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 02, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys28 amino acid residue in F9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22639855, 19699296, 15921378). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt F9 protein function. This variant has been observed in individual(s) with hemophilia B (PMID: 7937052, 22639855, 19699296, 15921378). This variant is also known as T111C; Cys-19Arg. ClinVar contains an entry for this variant (Variation ID: 10657). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 28 of the F9 protein (p.Cys28Arg). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and arginine. - |
Hereditary factor IX deficiency disease Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 11, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at