NM_005141.5:c.794C>T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_005141.5(FGB):c.794C>T(p.Pro265Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00425 in 1,597,176 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005141.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FGB | ENST00000302068.9 | c.794C>T | p.Pro265Leu | missense_variant | Exon 5 of 8 | 1 | NM_005141.5 | ENSP00000306099.4 | ||
FGB | ENST00000509493.1 | c.137C>T | p.Pro46Leu | missense_variant | Exon 3 of 6 | 5 | ENSP00000426757.1 | |||
FGB | ENST00000502545.5 | n.775C>T | non_coding_transcript_exon_variant | Exon 5 of 7 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00276 AC: 419AN: 151936Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00235 AC: 591AN: 251290Hom.: 0 AF XY: 0.00242 AC XY: 328AN XY: 135816
GnomAD4 exome AF: 0.00441 AC: 6373AN: 1445124Hom.: 20 Cov.: 27 AF XY: 0.00426 AC XY: 3067AN XY: 720022
GnomAD4 genome AF: 0.00276 AC: 419AN: 152052Hom.: 0 Cov.: 31 AF XY: 0.00219 AC XY: 163AN XY: 74310
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
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Congenital afibrinogenemia Pathogenic:1Benign:1
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not specified Uncertain:1Benign:1
Variant summary: FGB c.794C>T (p.Pro265Leu) results in a non-conservative amino acid change located in the C-terminal globular domain (IPR002181) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0024 in 251290 control chromosomes, predominantly at a frequency of 0.0044 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in FGB causing Afibrinogenemia, Congenital phenotype. c.794C>T has been reported in several heterozygous individuals affected with hypofibrinogenemia and various (suspected) bleeding/coagulation disorders (Brennan_2000, Morris_2009, Downes_2019, Almazni_2020, Preisler_2020). Large scale population studies demonstrated an association with slightly lower (~10%) fibrinogen levels (Wassel_2010, Huffman_2015, de Vries_2016). In addition, at least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated decreased clot formation and clot lysis in heterozygous patient samples, which corresponded to about 70% of the control values (Morris_2009). The following publications have been ascertained in the context of this evaluation (PMID: 31064749, 32935436, 10688828, 33477601, 26105150, 19420351, 20978265, 26561523). ClinVar contains an entry for this variant (Variation ID: 517313). Based on the evidence outlined above, the variant was classified as likely benign. -
Variant classified as Uncertain Significance - Favor Benign. The p.Pro265Leu (NM _005141.4 c.794C>T) variant in FGB has been reported in 3 compound heterozygous and 1 homozygous individuals with Hypofibrinogenemia or Chronic thromboembolic p ulmonary hypertension (CTEPH), though the additional variants found in heterozyg osity were not well-established pathogenic variants (Brennan 2000 and Morris 200 9). In vitro functional studies provide conflicting data (Brennan 2000 and Morri s 2009). This variant has been identified in 0.381% (254/66716) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs52828882, rs2227436, rs6054) as well as 5% of controls in the Brennan 2000 study. In summary, the clinical significance of the p.Pro265Leu variant is uncertain; however, based on population frequency and functional data we favor a benign interpretation. -
Abnormal bleeding Pathogenic:1
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Thrombus Uncertain:1
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FGB-related disorder Uncertain:1
The FGB c.794C>T variant is predicted to result in the amino acid substitution p.Pro265Leu. This variant, also described using legacy nomenclature as p.Pro235Leu, has been reported in individuals with hypofibrinogenemia, chronic thromboembolic pulmonary hypertension, or platelet defect (Brennan et al. 2000. PubMed ID: 10688828; Morris et al. 2009. PubMed ID: 19420351; Almazni et al. 2020. PubMed ID: 32935436). However, this variant has also been reported in healthy controls (Brennan et al. 2000. PubMed ID: 10688828). This variant is reported in 0.44% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant has conflicting interpretations of likely benign, uncertain significance, likely pathogenic, and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/517313/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Thrombocytopenia;C1458140:Abnormal bleeding Uncertain:1
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Hypofibrinogenemia Uncertain:1
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Afibrinogenemia Uncertain:1
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Familial dysfibrinogenemia Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at