rs137852259

Positions:

• chrX-139561821-G-A
• chrX-139561821-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The ENST00000218099.7(F9):​c.1136G>A​(p.Arg379Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,098,189 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. R379G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: F9 ENST00000218099.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.17

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 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in ENST00000218099.7
• 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, 0.933
• PP5: Variant X-139561821-G-A is Pathogenic according to our data. Variant chrX-139561821-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-139561821-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F9	NM_000133.4	c.1136G>A	p.Arg379Gln	missense_variant	8/8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.1022G>A	p.Arg341Gln	missense_variant	7/7		NP_001300842.1
F9	XM_005262397.5	c.1007G>A	p.Arg336Gln	missense_variant	7/7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.1136G>A	p.Arg379Gln	missense_variant	8/8	1	NM_000133.4	ENSP00000218099	P1
F9	ENST00000394090.2	c.1022G>A	p.Arg341Gln	missense_variant	7/7	1		ENSP00000377650
F9	ENST00000643157.1	n.1723+80G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098189 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363551

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor IX deficiency disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 11, 2022	Variant summary: F9 c.1136G>A (p.Arg379Gln) results in a conservative amino acid change located in the Trypsin-like serine protease domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function, while two tools predict the variant to be damaging or disease-causing. The variant was absent in 183173 control chromosomes. c.1136G>A has been reported in the literature in multiple individuals affected with Factor IX Deficiency (Hemophilia B) (e.g. Hamasaki-Katagiri_2012, Yu_2012, Agrawal_2022). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (e.g. Jin_2004, Mathur_1999). The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1988	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 26, 2018

The F9 c.1136G>A; p.Arg379Gln variant (rs137852259), also known as p.Arg333Gln or 31119G>A in traditional nomenclature, is reported in the literature in multiple individuals and families affected with moderate to severe hemophilia B (Chavali 2009, Hamasaki-Katagiri 2012, Lin 2018, Factor IX database and references therein). This variant is reported in ClinVar (Variation ID: 10613), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, other variants at this codon (p.Arg379Gly/Pro/Leu) have been reported in individuals with moderate to severe hemophilia B (Factor IX database and references therein). The arginine at codon 379 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Based on available information, this variant is considered to be pathogenic. References: Link to Factor IX database: http://www.factorix.org/ Chavali S et al. Hemophilia B is a quasi-quantitative condition with certain mutations showing phenotypic plasticity. Genomics. 2009 Dec;94(6):433-7. Hamasaki-Katagiri N et al. Analysis of F9 point mutations and their correlation to severity of haemophilia B disease. Haemophilia. 2012 Nov;18(6):933-40. Lin XY et al. Establishing a comprehensive genetic diagnosis strategy for hemophilia B and its application in Chinese population. Int J Lab Hematol. 2018 Apr;40(2):215-228. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg379 amino acid residue in F9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19699296). 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. ClinVar contains an entry for this variant (Variation ID: 10613). This variant is also known as p.Arg333Gln. This missense change has been observed in individuals with hemophilia B (PMID: 22639855). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 379 of the F9 protein (p.Arg379Gln). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2024

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.R333Q; This variant is associated with the following publications: (PMID: 34590426, 31064749, 22639855, 23683414, 29274203, 34272389, 28270892, 37445943, 15178576, 38783919, 34626083, 33760382, 28193338, 3181127, 17066096, 2270538, 8257988, 30992271, 27766048, 19699296, 10373456, 30771412) -

Hereditary factor VIII deficiency disease Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T;T
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	0.15	N;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.63
Sift	Benign	0.052	T;T
Sift4G	Benign	0.067	T;T
Polyphen		0.98	D;.
Vest4		0.31
MutPred		0.95		Loss of sheet (P = 0.1158);.;
MVP		1.0
MPC		1.4
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.81
gMVP		0.99

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: rs137852259; hg19: chrX-138643980; COSMIC: COSV54378521;