chrX-139530783-A-T
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000133.4(F9):c.19A>T(p.Ile7Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,209,789 control chromosomes in the GnomAD database, including 2 homozygotes. There are 489 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.00089 ( 0 hom., 28 hem., cov: 23)
Exomes 𝑓: 0.0013 ( 2 hom. 461 hem. )
Consequence
F9
NM_000133.4 missense
NM_000133.4 missense
Scores
1
6
10
Clinical Significance
Conservation
PhyloP100: 3.49
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 -20 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.025558144).
BP6
?
Variant X-139530783-A-T is Benign according to our data. Variant chrX-139530783-A-T is described in ClinVar as [Benign]. Clinvar id is 367997.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-139530783-A-T is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000888 (100/112563) while in subpopulation NFE AF= 0.00169 (90/53321). AF 95% confidence interval is 0.00141. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
BS2
?
High Hemizygotes in GnomAd at 28 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F9 | NM_000133.4 | c.19A>T | p.Ile7Phe | missense_variant | 1/8 | ENST00000218099.7 | |
F9 | NM_001313913.2 | c.19A>T | p.Ile7Phe | missense_variant | 1/7 | ||
F9 | XM_005262397.5 | c.19A>T | p.Ile7Phe | missense_variant | 1/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F9 | ENST00000218099.7 | c.19A>T | p.Ile7Phe | missense_variant | 1/8 | 1 | NM_000133.4 | P1 | |
F9 | ENST00000394090.2 | c.19A>T | p.Ile7Phe | missense_variant | 1/7 | 1 | |||
F9 | ENST00000479617.2 | n.26A>T | non_coding_transcript_exon_variant | 1/4 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000889 AC: 100AN: 112507Hom.: 0 Cov.: 23 AF XY: 0.000808 AC XY: 28AN XY: 34659
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GnomAD3 exomes AF: 0.000918 AC: 168AN: 183102Hom.: 0 AF XY: 0.000842 AC XY: 57AN XY: 67692
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GnomAD4 exome AF: 0.00131 AC: 1438AN: 1097226Hom.: 2 Cov.: 29 AF XY: 0.00127 AC XY: 461AN XY: 362702
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ClinVar
Significance: Benign
Submissions summary: Uncertain:1Benign:9
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary factor IX deficiency disease Uncertain:1Benign:4
Uncertain significance, no assertion criteria provided | clinical testing | ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | - | - - |
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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Benign, reviewed by expert panel | curation | ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen | Feb 09, 2024 | NM_000133.3:c.19A>T variant results in a missense change in the signal peptide. This variant is reported at a frequency of 0.001643 (152/92537 alleles with 57 hemizygotes) in the non-Finnish European population in gnomAD v2.1.1, meeting the BA1 cut-off of >= 0.0000556. At least 2 individuals with the variant and normal FIX levels from the literature and internal laboratory data are reported (PMID: 29296726) meeting the BS2 criterion. 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, BS2. - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 08, 2020 | - - |
F9-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 21, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
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 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | F9: BS1, BS2 - |
FACTOR IX POLYMORPHISM Benign:1
Benign, no assertion criteria provided | literature only | OMIM | Sep 01, 1989 | - - |
Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect;C5393318:Warfarin sensitivity, X-linked Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 15, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;.
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
T;D
Polyphen
B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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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