rs121913088
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_021870.3(FGG):c.902G>A(p.Arg301His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,272 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R301C) has been classified as Pathogenic.
Frequency
Consequence
NM_021870.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FGG | NM_021870.3 | c.902G>A | p.Arg301His | missense_variant | 8/9 | ENST00000336098.8 | NP_068656.2 | |
FGG | NM_000509.6 | c.902G>A | p.Arg301His | missense_variant | 8/10 | NP_000500.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FGG | ENST00000336098.8 | c.902G>A | p.Arg301His | missense_variant | 8/9 | 2 | NM_021870.3 | ENSP00000336829 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000800 AC: 2AN: 250136Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135184
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461026Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726788
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74448
ClinVar
Submissions by phenotype
Familial dysfibrinogenemia Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Oct 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 21, 2024 | Variant summary: FGG c.902G>A (p.Arg301His) results in a non-conservative amino acid change located in the Fibrinogen, alpha/beta/gamma chain, C-terminal globular domain (IPR002181) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250136 control chromosomes. c.902G>A has been reported in the literature in multiple individuals affected with Dysfibrinogenemia (examples: Smith_2018 and Wang_2018). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.901C>T, p.Arg301Cys), supporting the critical relevance of codon 301 to FGG protein function. The following publications have been ascertained in the context of this evaluation (PMID: 30349899, 29351094). ClinVar contains an entry for this variant (Variation ID: 16362). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 14, 2023 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 23, 2024 | Published functional studies suggest a damaging effect (PMID: 20508898); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.R275H; This variant is associated with the following publications: (PMID: 23683413, 30512152, 36964972, 34455742, 35063457, 7654933, 19132250, 3563970, 1455400, 2958955, 17604827, 30349899, 20546853, 30856382, 34355501, 29351094, 32877852, 20508898, 31064749) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 11, 2022 | PP3, PP5, PM1, PM2, PM5, PS3, PS4_moderate - |
Hypofibrinogenemia Pathogenic:1
Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
FIBRINOGEN HAIFA 1 Other:1
other, no assertion criteria provided | literature only | OMIM | Sep 19, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at