X-139561754-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000133.4(F9):c.1069G>A(p.Gly357Arg) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G357E) has been classified as Pathogenic.
Frequency
Consequence
NM_000133.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F9 | NM_000133.4 | c.1069G>A | p.Gly357Arg | missense_variant | 8/8 | ENST00000218099.7 | |
F9 | NM_001313913.2 | c.955G>A | p.Gly319Arg | missense_variant | 7/7 | ||
F9 | XM_005262397.5 | c.940G>A | p.Gly314Arg | missense_variant | 7/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F9 | ENST00000218099.7 | c.1069G>A | p.Gly357Arg | missense_variant | 8/8 | 1 | NM_000133.4 | P1 | |
F9 | ENST00000394090.2 | c.955G>A | p.Gly319Arg | missense_variant | 7/7 | 1 | |||
F9 | ENST00000643157.1 | n.1723+13G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
Hereditary factor IX deficiency disease Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. The variant has been confirmed to be de novo as shown in the table above In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with F9-related disorder (ClinVar ID: VCV000010611 / PMID: 7937052). Different missense changes at the same codon (p.Gly357Glu, p.Gly357Val) have been reported to be associated with F9-related disorder (ClinVar ID: VCV000010647 / PMID: 7937052). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1989 | - - |
Hereditary factor VIII deficiency disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at