rs137852283

Variant names:

• chrX-139561836-G-A
• rs137852283
• NM_000133.4:c.1151G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-139561836-G-A
• chrX-139561836-G-C
• chrX-139561836-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP2 BP4

The NM_000133.4(F9):​c.1151G>A​(p.Arg384Gln) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R384L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.50

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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 chrX-139561836-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 10668.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 162 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 2.1809 (below the threshold of 3.09). GenCC associations: The gene is linked to hemophilia B, symptomatic form of hemophilia B in female carriers, thrombophilia, X-linked, due to factor 9 defect, moderately severe hemophilia B, mild hemophilia B, severe hemophilia B.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34931195).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4	c.1151G>A	p.Arg384Gln	missense_variant	Exon 8 of 8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.1037G>A	p.Arg346Gln	missense_variant	Exon 7 of 7		NP_001300842.1
F9	XM_005262397.5	c.1022G>A	p.Arg341Gln	missense_variant	Exon 7 of 7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.1151G>A	p.Arg384Gln	missense_variant	Exon 8 of 8	1	NM_000133.4	ENSP00000218099.2
F9	ENST00000394090.2	c.1037G>A	p.Arg346Gln	missense_variant	Exon 7 of 7	1		ENSP00000377650.2
F9	ENST00000643157.1	n.1723+95G>A		intron_variant	Intron 6 of 6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 27, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thrombus Uncertain:1

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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.36	N;.
PhyloP100		1.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.14	N;N
REVEL	Benign	0.17
Sift	Benign	0.35	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.0060	B;.
Vest4		0.14
MutPred		0.55		Loss of helix (P = 0.1299);.;
MVP		0.90
MPC		0.76
ClinPred		0.15	T
GERP RS		2.9
Varity_R		0.34
gMVP		0.90
Mutation Taster		=75/25	polymorphism

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

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Other links and lift over

dbSNP: rs137852283; hg19: chrX-138643995;