FGA

Chr 4ARAD

fibrinogen alpha chain

Also known as: AMYLD2, Fib2

NCBI Gene: 2243 ENSG00000171560 UniProt: P02671

This gene encodes the alpha subunit of the coagulation factor fibrinogen, which is a component of the blood clot. Following vascular injury, the encoded preproprotein is proteolytically processed by thrombin during the conversion of fibrinogen to fibrin. Mutations in this gene lead to several disorders, including dysfibrinogenemia, hypofibrinogenemia, afibrinogenemia and renal amyloidosis. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that undergoes proteolytic processing. [provided by RefSeq, Jan 2016]

Primary Disease Associations & Inheritance

Afibrinogenemia, congenitalMIM #202400

Amyloidosis, hereditary systemic 2MIM #105200

Dysfibrinogenemia, congenitalMIM #616004

Hypodysfibrinogenemia, congenitalMIM #616004

UniProtCongenital afibrinogenemia

374

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— FGA

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Gene-Disease Validity (ClinGen)

congenital fibrinogen deficiency · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

90 Pathogenic / Likely Pathogenic· 220 VUS of 374 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Some data sources returned errors (1)

pubmed: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

1.02LOEUF

pLI 0.000

Z-score 1.46

OE 0.73 (0.53–1.02)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

-0.67Z-score

OE missense 1.09 (1.01–1.17)

498 obs / 457.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.73 (0.53–1.02)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.09 (1.01–1.17)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.11

0≤1.21.6

LoF obs/exp: 25 / 34.2Missense obs/exp: 498 / 457.6Syn Z: -1.12