X-139561805-G-T

Position:

• chrX-139561805-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000133.4(F9):​c.1120G>T​(p.Val374Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.67

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a chain Coagulation factor IXa heavy chain (size 234) in uniprot entity FA9_HUMAN there are 51 pathogenic changes around while only 0 benign (100%) in NM_000133.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-139561805-G-T is Pathogenic according to our data. Variant chrX-139561805-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 10639.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F9	NM_000133.4	c.1120G>T	p.Val374Phe	missense_variant	8/8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.1006G>T	p.Val336Phe	missense_variant	7/7		NP_001300842.1
F9	XM_005262397.5	c.991G>T	p.Val331Phe	missense_variant	7/7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.1120G>T	p.Val374Phe	missense_variant	8/8	1	NM_000133.4	ENSP00000218099.2
F9	ENST00000394090.2	c.1006G>T	p.Val336Phe	missense_variant	7/7	1		ENSP00000377650.2
F9	ENST00000643157.1	n.1723+64G>T		intron_variant

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 18, 2018

The F9 c.1120G>T; p.Val374Phe variant (rs137852271) is reported in the literature in multiple individuals affected with moderate to severe hemophilia B (Belvini 2005, Costa 2000, Giannelli 1994, Knobloch 1993, Winship 1990). This variant is reported in ClinVar (Variation ID: 10639), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 374 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this codon (c.1120G>A, p.Val374Ile) has been reported in individuals with moderate hemophilia B and is considered pathogenic (Giannelli 1994, Poort 1990). Based on available information, the p.Val374Phe variant is considered to be pathogenic. References: Belvini D et al. Molecular genotyping of the Italian cohort of patients with hemophilia B. Haematologica. 2005 May;90(5):635-42. Costa JM et al. Fast and efficient mutation detection method using multiplex PCR and cycle sequencing--application to haemophilia B. Thromb Haemost. 2000 Feb;83(2):244-7. Giannelli F et al. Haemophilia B: database of point mutations and short additions and deletions, fifth edition, 1994. Nucleic Acids Res. 1994 Sep;22(17):3534-46. Knobloch O et al. Recurrent mutations in the factor IX gene: founder effect or repeat de novo events. Investigation of the German haemophilia B population and review of de novo mutations. Hum Genet. 1993 Aug;92(1):40-8. Poort SR et al. Two mutations of the factor IX gene including a donor splice consensus deletion and a point mutation in a Dutch patient with severe hemophilia B. Thromb Haemost. 1990 Nov 30;64(3):379-84. Winship PR. Haemophilia B caused by mutation of a potential thrombin cleavage site in factor IX. Nucleic Acids Res. 1990 Mar 11;18(5):1310. -

Hereditary factor IX deficiency disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1991

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.78
MutPred		0.95		Loss of stability (P = 0.0938);.;
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.95
gMVP		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs137852271; hg19: chrX-138643964;