chr4-154587511-C-A
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Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_021871.4(FGA):c.510+1G>T variant causes a splice donor change. The variant allele was found at a frequency of 0.000115 in 1,613,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 30)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
FGA
NM_021871.4 splice_donor
NM_021871.4 splice_donor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.17
Genes affected
FGA (HGNC:3661): (fibrinogen alpha chain) 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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 22 ACMG points.
PVS1
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.6, offset of 4, new splice context is: taaGTatgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 4-154587511-C-A is Pathogenic according to our data. Variant chr4-154587511-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 16415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGA | NM_021871.4 | c.510+1G>T | splice_donor_variant | ENST00000403106.8 | |||
FGA | NM_000508.5 | c.510+1G>T | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGA | ENST00000403106.8 | c.510+1G>T | splice_donor_variant | 1 | NM_021871.4 | ||||
FGA | ENST00000651975.2 | c.510+1G>T | splice_donor_variant | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152072Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251372Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135858
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GnomAD4 exome AF: 0.000118 AC: 173AN: 1461558Hom.: 0 Cov.: 33 AF XY: 0.000111 AC XY: 81AN XY: 727092
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GnomAD4 genome AF: 0.0000789 AC: 12AN: 152072Hom.: 0 Cov.: 30 AF XY: 0.0000808 AC XY: 6AN XY: 74288
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial hypodysfibrinogenemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2004 | - - |
Familial visceral amyloidosis, Ostertag type;C0272350:Familial dysfibrinogenemia;C2584774:Congenital afibrinogenemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 05, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 25, 2022 | This variant is present in population databases (rs146387238, gnomAD 0.009%). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 16415). This variant is also known as IVS4+1G>T. Disruption of this splice site has been observed in individuals with hereditary fibrinogen abnormalities (PMID: 10891444, 30349899). This sequence change affects a donor splice site in intron 4 of the FGA gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. - |
Congenital afibrinogenemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2000 | - - |
Hypofibrinogenemia Pathogenic:1
Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
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DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at