X-139530832-T-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.68T>C(p.Leu23Pro) 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.98

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 hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000133.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant X-139530832-T-C is Pathogenic according to our data. Variant chrX-139530832-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2683971.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F9	NM_000133.4	c.68T>C	p.Leu23Pro	missense_variant	1/8	ENST00000218099.7
F9	NM_001313913.2	c.68T>C	p.Leu23Pro	missense_variant	1/7
F9	XM_005262397.5	c.68T>C	p.Leu23Pro	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F9	ENST00000218099.7	c.68T>C	p.Leu23Pro	missense_variant	1/8	1	NM_000133.4	P1
F9	ENST00000394090.2	c.68T>C	p.Leu23Pro	missense_variant	1/7	1
F9	ENST00000479617.2	n.75T>C		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary factor IX deficiency disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Jun 23, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.68	T;T
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.024	D;D
Polyphen		0.98	D;.
Vest4		0.89
MutPred		0.85		Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);
MVP		1.0
MPC		0.50
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.86
gMVP		0.87

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: rs1927328297; hg19: chrX-138612991;