chrX-139530816-T-C

Position:

• chrX-139530816-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000133.4(F9):​c.52T>C​(p.Cys18Arg) 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 (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.01

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant X-139530816-T-C is Pathogenic according to our data. Variant chrX-139530816-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 10568.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F9	NM_000133.4	c.52T>C	p.Cys18Arg	missense_variant	1/8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.52T>C	p.Cys18Arg	missense_variant	1/7		NP_001300842.1
F9	XM_005262397.5	c.52T>C	p.Cys18Arg	missense_variant	1/7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.52T>C	p.Cys18Arg	missense_variant	1/8	1	NM_000133.4	ENSP00000218099	P1
F9	ENST00000394090.2	c.52T>C	p.Cys18Arg	missense_variant	1/7	1		ENSP00000377650
F9	ENST00000479617.2	n.59T>C		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary factor IX deficiency disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;.
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.65	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.5	N;D
REVEL	Uncertain	0.59
Sift	Benign	0.053	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.59	P;.
Vest4		0.74
MutPred		0.80		Loss of catalytic residue at L19 (P = 0.0345);Loss of catalytic residue at L19 (P = 0.0345);
MVP		0.95
MPC		0.33
ClinPred		0.88	D
GERP RS		5.1
Varity_R		0.77
gMVP		0.89

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: rs387906474; hg19: chrX-138612975;