X-139530808-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000133.4(F9):c.44T>A(p.Ile15Asn) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.48

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F9	NM_000133.4	c.44T>A	p.Ile15Asn	missense_variant	1/8	ENST00000218099.7
F9	NM_001313913.2	c.44T>A	p.Ile15Asn	missense_variant	1/7
F9	XM_005262397.5	c.44T>A	p.Ile15Asn	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F9	ENST00000218099.7	c.44T>A	p.Ile15Asn	missense_variant	1/8	1	NM_000133.4	P1
F9	ENST00000394090.2	c.44T>A	p.Ile15Asn	missense_variant	1/7	1
F9	ENST00000479617.2	n.51T>A		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 01, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with F9-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with asparagine at codon 15 of the F9 protein (p.Ile15Asn). The isoleucine residue is weakly conserved and there is a large physicochemical difference between isoleucine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;.
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.78	T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.20	B;.
Vest4		0.69
MutPred		0.57		Loss of catalytic residue at L20 (P = 0.0297);Loss of catalytic residue at L20 (P = 0.0297);
MVP		0.93
MPC		0.37
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.69
gMVP		0.80

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: rs1927326780; hg19: chrX-138612967;