X-139551112-C-A

Position:

• chrX-139551112-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000133.4(F9):​c.571C>A​(p.Arg191Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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.

• Frequency: Genomes: not found (cov: 23)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.17

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F9	NM_000133.4	c.571C>A	p.Arg191Ser	missense_variant	6/8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.457C>A	p.Arg153Ser	missense_variant	5/7		NP_001300842.1
F9	XM_005262397.5	c.442C>A	p.Arg148Ser	missense_variant	5/7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.571C>A	p.Arg191Ser	missense_variant	6/8	1	NM_000133.4	ENSP00000218099	P1
F9	ENST00000394090.2	c.457C>A	p.Arg153Ser	missense_variant	5/7	1		ENSP00000377650
F9	ENST00000643157.1	n.1238C>A		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.74	T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.6	N;N
REVEL	Pathogenic	0.68
Sift	Benign	0.24	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.73	P;.
Vest4		0.67
MutPred		0.84		Gain of disorder (P = 0.0576);.;
MVP		1.0
MPC		1.7
ClinPred		0.87	D
GERP RS		4.0
Varity_R		0.55
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: rs137852237; hg19: chrX-138633271; COSMIC: COSV54378791; COSMIC: COSV54378791;