rs137852228

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PS4PP4_ModeratePP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000133.4(F9):c.224G>A (p.Arg75Gln) missense variant has a REVEL score of 0.904, which meets criteria for PP3. This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). Approximately 24 patients are reported in the literature with mild hemophilia B and this variant, meeting F9 phenotype criteria for PS4_Very strong (PMID:31064749, PMID:2066105, PMID:8314564, PMID:29296726, PMID:27213901, PMID:2773937). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Very strong, PP4_Moderate, PP3, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA255318/MONDO:0010604/080

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000036 ( 0 hom. 1 hem. )

Consequence

F9
NM_000133.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 7.32

Variant links:

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]

F9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 8 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4 link	c.224G>A	p.Arg75Gln	missense_variant	Exon 2 of 8	ENST00000218099.7	NP_000124.1	P00740-1
F9	NM_001313913.2 link	c.224G>A	p.Arg75Gln	missense_variant	Exon 2 of 7		NP_001300842.1	P00740-2
F9	XM_005262397.5 link	c.224G>A	p.Arg75Gln	missense_variant	Exon 2 of 7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
F9	ENST00000218099.7 link	c.224G>A	p.Arg75Gln	missense_variant	Exon 2 of 8	1	NM_000133.4	ENSP00000218099.2	P00740-1
F9	ENST00000394090.2 link	c.224G>A	p.Arg75Gln	missense_variant	Exon 2 of 7	1		ENSP00000377650.2	P00740-2
F9	ENST00000479617.2 link	n.231G>A		non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000547

AC:

AN:

182973

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67663

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1097542

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363114

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

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:

0.00000356

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary factor IX deficiency disease

Pathogenic:4

Oct 11, 2024

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_000133.4(F9):c.224G>A (p.Arg75Gln) missense variant has a REVEL score of 0.904, which meets criteria for PP3. This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). Approximately 24 patients are reported in the literature with mild hemophilia B and this variant, meeting F9 phenotype criteria for PS4_Very strong (PMID: 31064749, PMID: 2066105, PMID: 8314564, PMID: 29296726, PMID: 27213901, PMID: 2773937). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Very strong, PP4_Moderate, PP3, PM2_supporting. -

Sep 01, 1989

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: F9 c.224G>A (p.Arg75Gln) results in a conservative amino acid change located in the Gamma-carboxyglutamic acid-rich (GLA) domain (IPR000294) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182973 control chromosomes (gnomAD). c.224G>A has been reported in the literature in multiple individuals affected with Factor IX Deficiency (Hemophilia B) (Chavali_2009, Hamasaki-Katagiri_2012, Meireles_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19699296, 22639855, 28722788). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=2) and likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:3

Sep 10, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16999730, 33314404, 2773937, 2066105, 31064749, 19699296, 30817849, 32224444, 24375831, 22639855) -

May 29, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM1_supporting, PM2_moderate, PS4_moderate -

Apr 17, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F9 c.224G>A; p.Arg75Gln variant (rs137852228) has been described in several individuals with mild hemophilia B (see link to Factor IX database and references therein). It is reported in ClinVar (Variation ID: 10573) and is observed at a low overall frequency of 0.0006% (1/178366 alleles) in the Genome Aggregation Database. The arginine at codon 75 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant to be deleterious. Additionally, other variants at this position (p.Arg75Gly, p. Arg75Pro) have been observed in individuals affected with hemophilia B and are considered pathogenic (see link to Factor IX database and references therein, Martensson 2016). Based on available information, this variant is considered likely pathogenic. References: Link to Factor IX database: http://www.factorix.org/ Martensson A et al. Mutation analysis of Swedish haemophilia B families - high frequency of unique mutations. Haemophilia. 2016 May;22(3):440-5. -

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

Pathogenic:1

Aug 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt F9 protein function. ClinVar contains an entry for this variant (Variation ID: 10573). This variant is also known as Arg29Gln. This missense change has been observed in individuals with hemophilia B (PMID: 2066105, 2773937, 19699296, 22639855, 24375831). This variant is present in population databases (rs137852228, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 75 of the F9 protein (p.Arg75Gln). -

Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect;C5393318:Warfarin sensitivity, X-linked

Pathogenic:1

Jan 10, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary factor VIII deficiency disease

Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.67

T;T

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

M;M

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.1

D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;.

Vest4

0.62

MutPred

0.92

Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);

MVP

1.0

MPC

0.16

ClinPred

0.92

GERP RS

4.3

Varity_R

0.83

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over