chr4-154589513-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_021871.4(FGA):c.104G>A(p.Arg35His) variant causes a missense change. The variant allele was found at a frequency of 0.0000235 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_021871.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251286Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135830
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461692Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19AN XY: 727160
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74338
ClinVar
Submissions by phenotype
Familial dysfibrinogenemia Pathogenic:3
Variant summary: FGA c.104G>A (p.Arg35His) results in a non-conservative amino acid change in 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 1.2e-05 in 251286 control chromosomes (gnomAD). c.104G>A has been reported in the literature in multiple individuals affected with Congenital Dysfibrinogenemia (e.g. Simurda_2020, Szanto_2021, Zhou_2021), including at least one homozygote (Alving_1987). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This FGA missense variant has been identified in the heterozygous state in multiple individuals with congenital dysfibrinogenemia, and is also reported in individuals with FGA-related congenital fibrinogen defects due to biallelic variants. This variant (rs121909607) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 4/282670 total alleles; 0.0014%; no homozygotes). It has been reported in ClinVar7 (Variation ID 16404). Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is evolutionarily conserved across all species assessed. Functional studies support that this missense change impacts protein function. We consider c.104G>A in FGA to be pathogenic. -
The FGA c.104G>A variant is classified as Pathogenic (PS1, PS4, PM1, PM2) The FGA c.104G>A variant is a single nucleotide change in exon 2/6 of the FGA gene, which is predicted to change the amino acid arginine at position 35 in the protein to histidine. The variant has been reported in probands with a clinical presentation of MIM: 616004 (PS4). The variant is rare in population databases (gnomAD allele frequency = 0.0013%; 2 het and 0 hom in 152172 sequenced alleles; highest frequency = 0.0024%, African/African American population) (PM2). Detected in 7x patients with disease in PMID 31064749. This variant is located in a conserved region (PM1). (PMID:34275736) This variant results in the same amino acid change as a previously established variant (PS1). The variant has been reported in dbSNP (rs121909607) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 16404). It has not been reported in HGMD. -
not provided Pathogenic:2
Published functional studies suggest a damaging effect: impaired thrombin polymerization, reduced fibrinogen clottability, reduced fibrinolysis velocity, and delayed release of fibrinopeptide A (PMID: 6830702, 22967385, 22880226); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as R16H using alternate nomenclature; This variant is associated with the following publications: (PMID: 32877852, 33822462, 33443927, 34275736, 32939696, 23962069, 22880226, 22967385, 6830702, 27684817, 6191801, 2738154, 9391726, 25320241, 26577257, 29070135, 29869737, 30856382, 31314131, 30332696, 32166693, 30349899, 2379562, 35949040, 35975558, 31064749, 3618591, 34455742, 7298640, 22169505) -
PM1, PM2_moderate, PM5, PS3, PS4_moderate -
Familial visceral amyloidosis, Ostertag type;C0272350:Familial dysfibrinogenemia;C2584774:Congenital afibrinogenemia Pathogenic:1
- -
FGA-related disorder Pathogenic:1
The FGA c.104G>A variant is predicted to result in the amino acid substitution p.Arg35His. This variant, also referred to as p.Arg16His using legacy nomenclature, has been reported in many patients to be causative for autosomal dominant congenital dysfibrinogenemia (Casini et al. 2015. PubMed ID: 25320241; Siebenlist et al. 1988. PubMed ID: 3345340; Smith et al. 2018. PubMed ID: 30349899; Shapiro et al. 2013. PubMed ID: 23061815). Other missense variants affecting this amino acid (p.Arg35Cys, p.Arg35Ser, p.Arg35Pro) have also been reported in patients with dysfibrinogenemia, suggesting p.Arg35 is important for proper FGA protein function (Miesbach et al. 2010. PubMed ID: 19923982; Shapiro et al. 2013. PubMed ID: 23061815). This variant is reported in 0.0031% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -
Abnormal bleeding Pathogenic:1
- -
Hypofibrinogenemia Pathogenic:1
- -
Dysfibrinogenemia Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at