chr4-154563137-AT-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_005141.5(FGB):c.114+11del variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,260,146 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
FGB
NM_005141.5 splice_donor_region, intron
NM_005141.5 splice_donor_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.610
Genes affected
FGB (HGNC:3662): (fibrinogen beta chain) The protein encoded by this gene is the beta component of fibrinogen, a blood-borne glycoprotein comprised of three pairs of nonidentical polypeptide chains. Following vascular injury, fibrinogen is cleaved by thrombin to form fibrin which is the most abundant component of blood clots. In addition, various cleavage products of fibrinogen and fibrin regulate cell adhesion and spreading, display vasoconstrictor and chemotactic activities, and are mitogens for several cell types. Fibrinogen serves key roles in hemostasis and antimicrobial host defense. Mutations in this gene lead to several disorders, including afibrinogenemia, dysfibrinogenemia, hypodysfibrinogenemia and thrombotic tendency. [provided by RefSeq, Aug 2020]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGB | NM_005141.5 | c.114+11del | splice_donor_region_variant, intron_variant | ENST00000302068.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGB | ENST00000302068.9 | c.114+11del | splice_donor_region_variant, intron_variant | 1 | NM_005141.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 151778Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000113 AC: 18AN: 158840Hom.: 0 AF XY: 0.000119 AC XY: 10AN XY: 83696
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GnomAD4 exome AF: 0.000108 AC: 120AN: 1108252Hom.: 0 Cov.: 15 AF XY: 0.0000892 AC XY: 50AN XY: 560392
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GnomAD4 genome ? AF: 0.000105 AC: 16AN: 151894Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7AN XY: 74238
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 25, 2022 | Variant summary: FGB c.114+11delT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 158840 control chromosomes. This frequency does not allow conclusions about variant significance. To our knowledge, no occurrence of c.114+11delT in individuals affected with Afibrinogenemia, Congenital and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Congenital afibrinogenemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at