chrX-139561566-G-T

Position:

• chrX-139561566-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP5_Moderate

The NM_000133.4(F9):​c.881G>T​(p.Arg294Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R294G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.44

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 Likely_pathogenic. Variant got 8 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP5: Variant X-139561566-G-T is Pathogenic according to our data. Variant chrX-139561566-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2138741.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.881G>T	p.Arg294Leu	missense_variant	8/8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.767G>T	p.Arg256Leu	missense_variant	7/7		NP_001300842.1
F9	XM_005262397.5	c.752G>T	p.Arg251Leu	missense_variant	7/7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.881G>T	p.Arg294Leu	missense_variant	8/8	1	NM_000133.4	ENSP00000218099.2
F9	ENST00000394090.2	c.767G>T	p.Arg256Leu	missense_variant	7/7	1		ENSP00000377650.2
F9	ENST00000643157.1	n.1548G>T		non_coding_transcript_exon_variant	6/7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000264

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 28, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg294Gln amino acid residue in F9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2472424, 19699296, 22103590, 22544209, 24375831, 29993188; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individuals with hemophilia B (PMID: 22103590, 24375831). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 294 of the F9 protein (p.Arg294Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.58
Sift	Benign	0.18	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.45	B;.
Vest4		0.23
MutPred		0.72		Loss of disorder (P = 0.0344);.;
MVP		0.99
MPC		1.8
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.90
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs137852249; hg19: chrX-138643725;