rs112057482
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_000133.4(F9):c.1095A>G(p.Ser365=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,210,305 control chromosomes in the GnomAD database, including 19 homozygotes. There are 681 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.0095 ( 9 hom., 290 hem., cov: 22)
Exomes 𝑓: 0.0012 ( 10 hom. 391 hem. )
Consequence
F9
NM_000133.4 synonymous
NM_000133.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.64
Genes affected
F9 (HGNC:3551): (coagulation factor IX) This gene encodes vitamin K-dependent coagulation factor IX that circulates in the blood as an inactive zymogen. This factor is converted to an active form by factor XIa, which excises the activation peptide and thus generates a heavy chain and a light chain held together by one or more disulfide bonds. The role of this activated factor IX in the blood coagulation cascade is to activate factor X to its active form through interactions with Ca+2 ions, membrane phospholipids, and factor VIII. Alterations of this gene, including point mutations, insertions and deletions, cause factor IX deficiency, which is a recessive X-linked disorder, also called hemophilia B or Christmas disease. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Sep 2015]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.93).
BP6
?
Variant X-139561780-A-G is Benign according to our data. Variant chrX-139561780-A-G is described in ClinVar as [Benign]. Clinvar id is 368002.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-139561780-A-G is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-1.64 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00949 (1064/112075) while in subpopulation AFR AF= 0.0321 (990/30810). AF 95% confidence interval is 0.0305. There are 9 homozygotes in gnomad4. There are 290 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd at 9 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F9 | NM_000133.4 | c.1095A>G | p.Ser365= | synonymous_variant | 8/8 | ENST00000218099.7 | |
F9 | NM_001313913.2 | c.981A>G | p.Ser327= | synonymous_variant | 7/7 | ||
F9 | XM_005262397.5 | c.966A>G | p.Ser322= | synonymous_variant | 7/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F9 | ENST00000218099.7 | c.1095A>G | p.Ser365= | synonymous_variant | 8/8 | 1 | NM_000133.4 | P1 | |
F9 | ENST00000394090.2 | c.981A>G | p.Ser327= | synonymous_variant | 7/7 | 1 | |||
F9 | ENST00000643157.1 | n.1723+39A>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00948 AC: 1062AN: 112024Hom.: 9 Cov.: 22 AF XY: 0.00845 AC XY: 289AN XY: 34200
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GnomAD3 exomes AF: 0.00290 AC: 532AN: 183190Hom.: 2 AF XY: 0.00199 AC XY: 135AN XY: 67676
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GnomAD4 exome AF: 0.00123 AC: 1355AN: 1098230Hom.: 10 Cov.: 31 AF XY: 0.00108 AC XY: 391AN XY: 363592
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GnomAD4 genome ? AF: 0.00949 AC: 1064AN: 112075Hom.: 9 Cov.: 22 AF XY: 0.00846 AC XY: 290AN XY: 34261
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ClinVar
Significance: Benign
Submissions summary: Benign:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary factor IX deficiency disease Benign:2
Benign, reviewed by expert panel | curation | ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen | Feb 09, 2024 | The NM_000133.3:c.1095A>G variant predicts a synonymous change, Ser365=. It is reported at a high frequency of 0.03271 (622/19015 alleles with 172 hemizygotes) in the African subpopulation in gnomAD v2.1.1, meeting the BA1 cut-off of >=0.0000556. The variant is not predicted to impact splicing, and the nucleotide position at which this variant occurs is not highly conserved, meeting the BP4 and BP7 criteria. To the best of our knowledge, the variant has not been reported in male patients with Hemophilia B. In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: BA1, BP4, BP7. - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 03, 2019 | - - |
Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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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