X-139560852-G-C

Position:

• chrX-139560852-G-C

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.835G>C​(p.Ala279Pro) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.12

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, 0.975
• PP5: Variant X-139560852-G-C is Pathogenic according to our data. Variant chrX-139560852-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1477908.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.835G>C	p.Ala279Pro	missense_variant	7/8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.721G>C	p.Ala241Pro	missense_variant	6/7		NP_001300842.1
F9	XM_005262397.5	c.706G>C	p.Ala236Pro	missense_variant	6/7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.835G>C	p.Ala279Pro	missense_variant	7/8	1	NM_000133.4	ENSP00000218099.2
F9	ENST00000394090.2	c.721G>C	p.Ala241Pro	missense_variant	6/7	1		ENSP00000377650.2
F9	ENST00000643157.1	n.1502G>C		non_coding_transcript_exon_variant	5/7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 11, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala279 amino acid residue in F9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2066105, 23093250, 27529981, 27865967, 29656491). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt F9 protein function. This variant has not been reported in the literature in individuals affected with F9-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with proline at codon 279 of the F9 protein (p.Ala279Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.021	D;T
Polyphen		0.88	P;.
Vest4		0.90
MutPred		0.85		Gain of glycosylation at T276 (P = 0.0564);.;
MVP		1.0
MPC		1.9
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.98
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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-138643011;