X-139551218-G-T

Variant names:

• chrX-139551218-G-T
• rs137852241
• NM_000133.4:c.677G>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000133.4(F9):​c.677G>T​(p.Arg226Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: Not reported in ClinVar
• 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.

• PM1: In a disulfide_bond Interchain (between light and heavy chains) (size 157) in uniprot entity FA9_HUMAN there are 19 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4	c.677G>T	p.Arg226Leu	missense_variant	Exon 6 of 8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.563G>T	p.Arg188Leu	missense_variant	Exon 5 of 7		NP_001300842.1
F9	XM_005262397.5	c.548G>T	p.Arg183Leu	missense_variant	Exon 5 of 7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.677G>T	p.Arg226Leu	missense_variant	Exon 6 of 8	1	NM_000133.4	ENSP00000218099.2
F9	ENST00000394090.2	c.563G>T	p.Arg188Leu	missense_variant	Exon 5 of 7	1		ENSP00000377650.2
F9	ENST00000643157.1	n.1344G>T		non_coding_transcript_exon_variant	Exon 4 of 7

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.88	P;.
Vest4		0.91
MutPred		0.94		Loss of catalytic residue at R226 (P = 0.0341);.;
MVP		1.0
MPC		1.1
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.94
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: rs137852241; hg19: chrX-138633377; COSMIC: COSV54380883; COSMIC: COSV54380883;