X-139530748-A-G

Variant names:

• chrX-139530748-A-G
• rs1927322926
• NM_000133.4:c.-17A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_000133.4(F9):​c.-17A>G variant causes a 5 prime UTR change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: F9 NM_000133.4 5_prime_UTR
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.60

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-139530748-A-G is Pathogenic according to our data. Variant chrX-139530748-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4	c.-17A>G		5_prime_UTR_variant	Exon 1 of 8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.-17A>G		5_prime_UTR_variant	Exon 1 of 7		NP_001300842.1
F9	XM_005262397.5	c.-17A>G		5_prime_UTR_variant	Exon 1 of 7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099	c.-17A>G		5_prime_UTR_variant	Exon 1 of 8	1	NM_000133.4	ENSP00000218099.2
F9	ENST00000394090.2	c.-17A>G		upstream_gene_variant		1		ENSP00000377650.2
F9	ENST00000479617.2	n.-10A>G		upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 24

Bravo AF: 0.0000453

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect Pathogenic:1

Jan 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Studies have shown that this variant does not significantly alter or has an unclear effect on F9 gene expression (PMID: 31395865). This variant occurs in a non-coding region of the F9 gene. It does not change the encoded amino acid sequence of the F9 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hemophilia B (PMID: 2917196, 17014892). This variant is also known as A13G. ClinVar contains an entry for this variant (Variation ID: 10646). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Jul 11, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PM1, PM2, PS4_moderate -

Hemophilia B leyden Pathogenic:1

Feb 15, 1989

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.75

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1927322926; hg19: chrX-138612907;