chr4-154565796-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_005141.5(FGB):c.115-12C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000611 in 1,613,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00057 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00061 ( 0 hom. )
Consequence
FGB
NM_005141.5 splice_polypyrimidine_tract, intron
NM_005141.5 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00001352
2
Clinical Significance
Conservation
PhyloP100: 0.561
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 Likely_benign. Variant got -3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
?
Variant 4-154565796-C-T is Benign according to our data. Variant chr4-154565796-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 901358.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGB | NM_005141.5 | c.115-12C>T | splice_polypyrimidine_tract_variant, intron_variant | ENST00000302068.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGB | ENST00000302068.9 | c.115-12C>T | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_005141.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000572 AC: 87AN: 152206Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000499 AC: 124AN: 248346Hom.: 0 AF XY: 0.000542 AC XY: 73AN XY: 134630
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GnomAD4 exome AF: 0.000615 AC: 898AN: 1461004Hom.: 0 Cov.: 30 AF XY: 0.000641 AC XY: 466AN XY: 726854
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GnomAD4 genome ? AF: 0.000571 AC: 87AN: 152324Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44AN XY: 74486
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Congenital afibrinogenemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 06, 2023 | Variant summary: FGB c.115-12C>T alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation 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 0.0005 in 248346 control chromosomes. To our knowledge, no occurrence of c.115-12C>T in individuals affected with Congenital Afibrinogenemia and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at