X-139530846-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000133.4(F9):c.82T>C(p.Cys28Arg) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C28Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.53

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 2 benign, 1 uncertain in NM_000133.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant X-139530846-T-C is Pathogenic according to our data. Variant chrX-139530846-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 10657.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.82T>C	p.Cys28Arg	missense_variant	1/8	ENST00000218099.7
F9	NM_001313913.2	c.82T>C	p.Cys28Arg	missense_variant	1/7
F9	XM_005262397.5	c.82T>C	p.Cys28Arg	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F9	ENST00000218099.7	c.82T>C	p.Cys28Arg	missense_variant	1/8	1	NM_000133.4	P1
F9	ENST00000394090.2	c.82T>C	p.Cys28Arg	missense_variant	1/7	1
F9	ENST00000479617.2	n.89T>C		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 02, 2021

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys28 amino acid residue in F9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22639855, 19699296, 15921378). 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 not expected to disrupt F9 protein function. This variant has been observed in individual(s) with hemophilia B (PMID: 7937052, 22639855, 19699296, 15921378). This variant is also known as T111C; Cys-19Arg. ClinVar contains an entry for this variant (Variation ID: 10657). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 28 of the F9 protein (p.Cys28Arg). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and arginine. -

Hereditary factor IX deficiency disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 11, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Benign	18
Dann	Benign	0.91
DEOGEN2	Uncertain	0.44	T;.
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.45	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.60	N;N
REVEL	Uncertain	0.62
Sift	Benign	0.53	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.0020	B;.
Vest4		0.68
MutPred		0.89		Loss of catalytic residue at V30 (P = 0.0571);Loss of catalytic residue at V30 (P = 0.0571);
MVP		1.0
MPC		0.13
ClinPred		0.22	T
GERP RS		4.0
Varity_R		0.67
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: rs387906481; hg19: chrX-138613005;