rs137852241

Positions:

• chrX-139551218-G-A
• chrX-139551218-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000133.4(F9):​c.677G>A​(p.Arg226Gln) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R226G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 5.36

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-139551218-G-A is Pathogenic according to our data. Variant chrX-139551218-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10591.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.677G>A	p.Arg226Gln	missense_variant	6/8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.563G>A	p.Arg188Gln	missense_variant	5/7		NP_001300842.1
F9	XM_005262397.5	c.548G>A	p.Arg183Gln	missense_variant	5/7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.677G>A	p.Arg226Gln	missense_variant	6/8	1	NM_000133.4	ENSP00000218099	P1
F9	ENST00000394090.2	c.563G>A	p.Arg188Gln	missense_variant	5/7	1		ENSP00000377650
F9	ENST00000643157.1	n.1344G>A		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

F9-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2024

The F9 c.677G>A variant is predicted to result in the amino acid substitution p.Arg226Gln. This variant, and other substitutions of amino acid residue p.Arg226, including p.Arg226Gly, p.Arg226Trp, p.Arg226Pro, and p.Arg226Leu, have been reported in many patients with mostly severe hemophilia B (see the Factor IX Gene (F9) Variant Database, http://www.factorix.org/; Hamasaki-Katagiri et al. 2012. PubMed ID: 22639855; Giannelli et al. 1994. PubMed ID: 7937052; Huang et al. 2020. PubMed ID: 32875744). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Hereditary factor IX deficiency disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Diagnostics Department, Viafet Genomics Laboratory

Jan 11, 2016

Viafet Genomics Laboratory has identified this variant in a female proband whose male offspring is presenting with Hemophilia B. This variant has been identified in several patients affected with Hemophilia B (PMIDs: 22639855 and 32875744). -

Hemophilia b(m) Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.74	T;T
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	0.99	A;A
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.86
MutPred		0.95		Loss of catalytic residue at R226 (P = 0.0625);.;
MVP		1.0
MPC		1.7
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.75
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137852241; hg19: chrX-138633377;