NM_021871.4:c.502C>T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_021871.4(FGA):c.502C>T(p.Arg168*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000149 in 1,613,652 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 (★★).
Frequency
Consequence
NM_021871.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 151954Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251358Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135846
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461698Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11AN XY: 727160
GnomAD4 genome AF: 0.0000197 AC: 3AN: 151954Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1AN XY: 74204
ClinVar
Submissions by phenotype
Congenital afibrinogenemia Pathogenic:2
The c.502C>T, p.Arg168ter variant has been seen in the homozygous state in four individuals: one Norwegian (Fellowes et al., 2000) and three Sardinian (Asselta et al., 2001), who were diagnosed with congenital afibrinogenemia. All these individuals had immunologically very low; to undetectable fibrinogen levels suggesting that loss-of-function is a mechanism of disease. Furthermore, this variant was shown to co-segregate with disease and family members who were heterozygous for this variant were unaffected (Fellowes et al., 2000). Arginine at position 168 is evolutionarily conserved and it is present within the coil-coil domain of the protein. This domain is critical for protein assembly. Indeed, an in vitro study using the p.Arg168ter variant showed an absence of secreted fibrinogen because of its inability to assemble with the other fibrinogen subunits (β and γ) (Asselta et al., 2001). This variant is either absent or present at a very low frequency, with no homozygotes, in the population databases (1000 Genome, Exome Sequencing Project and ExAC). In summary, this variant meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing. -
PM2_Supporting+PVS1_Strong+PM3_Strong+PP1_Moderate -
Familial visceral amyloidosis, Ostertag type;C0272350:Familial dysfibrinogenemia;C2584774:Congenital afibrinogenemia Pathogenic:1
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not provided Pathogenic:1
This variant has been reported in the homozygous or compound heterozygous state in individuals affected with afibrinogenaemia (PMID: 10887149, 26763372). ClinVar contains an entry for this variant (Variation ID: 402230). Analysis of patient-derived plasma was unable to detect fibrinogen via clotting and immunological methods in an individual carrying this variant along with another rare FGA variant (PMID: 26763372). For these reasons, this variant has been classified as Pathogenic. This sequence change results in a premature translational stop signal in the FGA gene (p.Arg168*). This is expected to delete the last 477 amino acids (~74%) of the FGA protein. This variant is present in population databases (rs755117226, ExAC 0.001%). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at