X-139561565-C-T

Variant names:

• chrX-139561565-C-T
• rs137852248
• NM_000133.4:c.880C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS4 PVS1_Strong PP4_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The F9 c.880C>T (Arg294Ter) variant occurs in exon 8/8 of the F9 gene, and NMD is not predicted. PVS1_Strong is applied based on truncation of the Peptidase S1 domain. This variant is completely absent from gnomAD v2.1.1 and v3.1.1, meeting PM2_Supporting criteria. Over 90 patients have been reported in the literature and the EAHAD database with hemophilia B in the moderate-severe range and history of inhibitors to factor replacement products are reported, meeting PP4_Moderate and PS4_Very strong (selected PMIDs: 29296726, 8217825, 8314564). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_VeryStrong, PVS1_Strong, PP4_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA255344/MONDO:0010604/080

• Frequency: Genomes: not found (cov: 23)
• Consequence: F9 NM_000133.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 1.09
• Publications: 13 publications found

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]

F9 Gene-Disease associations (from GenCC):

• hemophilia B

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• mild hemophilia B

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• moderately severe hemophilia B

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• severe hemophilia B

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• symptomatic form of hemophilia B in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• thrombophilia, X-linked, due to factor 9 defect

  Inheritance: XL Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000133.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F9	NM_000133.4	MANE Select	c.880C>T	p.Arg294*	stop_gained	Exon 8 of 8	NP_000124.1
	F9	NM_001313913.2		c.766C>T	p.Arg256*	stop_gained	Exon 7 of 7	NP_001300842.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F9	ENST00000218099.7	TSL:1 MANE Select	c.880C>T	p.Arg294*	stop_gained	Exon 8 of 8	ENSP00000218099.2
	F9	ENST00000394090.2	TSL:1	c.766C>T	p.Arg256*	stop_gained	Exon 7 of 7	ENSP00000377650.2
	F9	ENST00000643157.1		n.1547C>T		non_coding_transcript_exon	Exon 6 of 7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000387 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary factor IX deficiency disease Pathogenic:4

Apr 01, 1989

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Dec 27, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22544209, 26612714). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000010587 /PMID: 2270538). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Feb 09, 2024

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The F9 c.880C>T (Arg294Ter) variant occurs in exon 8/8 of the F9 gene, and NMD is not predicted. PVS1_Strong is applied based on truncation of the Peptidase S1 domain. This variant is completely absent from gnomAD v2.1.1 and v3.1.1, meeting PM2_Supporting criteria. Over 90 patients have been reported in the literature and the EAHAD database with hemophilia B in the moderate-severe range and history of inhibitors to factor replacement products are reported, meeting PP4_Moderate and PS4_Very strong (selected PMIDs: 29296726, 8217825, 8314564). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_VeryStrong, PVS1_Strong, PP4_Moderate, PM2_Supporting.

Jul 01, 2023

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

not provided Pathogenic:2

Oct 03, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation, as the last 168 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 28270892, 27109384, 38196513, 33760382, 2270538, 31064749, 35842956, 26612714, 22618954, 8314564, 8217825, 34590426, 36347023, 22544209, 10595634, 24375831, 33999344)

Mar 21, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP5, PM2_moderate, PS4_moderate, PVS1

not specified Pathogenic:1

Jun 13, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F9 c.880C>T; p.Arg294Ter variant (rs137852248), also known as p.Arg248Ter in traditional nomenclature, is reported in the literature in multiple individuals affected with moderate to severe hemophilia B (Factor IX database and references therein). This variant is reported as pathogenic in ClinVar (Variation ID: 10587), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the F9 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein, and other downstream nonsense variants have been reported in individuals with hemophilia and are considered pathogenic (Factor IX database and references therein). Based on available information, the p.Arg294Ter variant is considered to be pathogenic. References: Factor IX database: http://www.factorix.org/

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

Jul 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg294*) in the F9 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 168 amino acid(s) of the F9 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with haemophilia (PMID: 2270538, 8217825, 8314564, 10595634, 22544209, 23093250, 24375831, 26612714). This variant is also known as p.Arg248*. ClinVar contains an entry for this variant (Variation ID: 10587). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.23	N
PhyloP100		1.1
Vest4		0.89
GERP RS		3.5
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs137852248; hg19: chrX-138643724;