X-139551113-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS4PM1_StrongPP4_ModeratePP3

This summary comes from the ClinGen Evidence Repository: The NM_000133.3(F9):c.572G>A predicts a missense change, Arg191His, at the activation residue. This residue is a site for cleavage by FXIa in order to activate FIX and therefore critical for protein function, which meets criteria for PM1_Strong. Over 100 patients meet the F9 phenotype criteria have been reported in the literature (selected PMIDs: 7873393,1972560, 26782891, 27865967, 24375831), meeting PS4_Very strong and PP4_Moderate. The variant has a REVEL score of 0.73 (threshold >0.6), meeting PP3. In summary, the variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency VCEP for F9: PS4_Very Strong, PM1_Strong, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA255342/MONDO:0010604/080

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 2 hem. )

Consequence

F9
NM_000133.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:9

Conservation

PhyloP100: 4.31

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

hemophilia B
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
mild hemophilia B
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
moderately severe hemophilia B
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
severe hemophilia B
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
symptomatic form of hemophilia B in female carriers
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
thrombophilia, X-linked, due to factor 9 defect
Inheritance: XL Classification: LIMITED Submitted by: ClinGen

F9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PS4

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

PM1

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.572G>A	p.Arg191His	missense_variant	Exon 6 of 8	ENST00000218099.7	NP_000124.1	P00740-1
F9	NM_001313913.2 link	c.458G>A	p.Arg153His	missense_variant	Exon 5 of 7		NP_001300842.1	P00740-2
F9	XM_005262397.5 link	c.443G>A	p.Arg148His	missense_variant	Exon 5 of 7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
F9	ENST00000218099.7 link	c.572G>A	p.Arg191His	missense_variant	Exon 6 of 8	1	NM_000133.4	ENSP00000218099.2	P00740-1
F9	ENST00000394090.2 link	c.458G>A	p.Arg153His	missense_variant	Exon 5 of 7	1		ENSP00000377650.2	P00740-2
F9	ENST00000643157.1 link	n.1239G>A		non_coding_transcript_exon_variant	Exon 4 of 7

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111818

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000545

AC:

AN:

183455

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1097762

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

363126

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26397

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19380

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54139

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00000356

AC:

AN:

841678

Other (OTH)

AF:

0.00

AC:

AN:

46089

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111818

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34006

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30766

American (AMR)

AF:

0.00

AC:

AN:

10531

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3565

South Asian (SAS)

AF:

0.00

AC:

AN:

2648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5999

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53215

Other (OTH)

AF:

0.00

AC:

AN:

1513

Alfa

AF:

0.00000773

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary factor IX deficiency disease

Pathogenic:5

Nov 15, 1990

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 09, 2024

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000133.3(F9):c.572G>A predicts a missense change, Arg191His, at the activation residue. This residue is a site for cleavage by FXIa in order to activate FIX and therefore critical for protein function, which meets criteria for PM1_Strong. Over 100 patients meet the F9 phenotype criteria have been reported in the literature (selected PMIDs: 7873393,1972560, 26782891, 27865967, 24375831), meeting PS4_Very strong and PP4_Moderate. The variant has a REVEL score of 0.73 (threshold >0.6), meeting PP3. In summary, the variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency VCEP for F9: PS4_Very Strong, PM1_Strong, PP4_Moderate, PP3. -

Jun 27, 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.572G>A (p.Arg191His) results in a non-conservative amino acid change in the encoded protein sequence. Three 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 183455 control chromosomes. c.572G>A has been reported in the literature in multiple individuals affected with Factor IX Deficiency (Hemophilia B) (Example: (Green_1992, Li_2014). These data indicate that the variant is very likely to be associated with disease. In addition, another missense variant in the same residue (p.Arg191Cys) has been classified as pathogenic in our laboratory, supporting the functional importance of this residue of the protein. 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: 1615486, 24375831). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 01, 2019

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

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

Pathogenic:1

Jul 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 191 of the F9 protein (p.Arg191His). This variant is present in population databases (rs137852238, gnomAD 0.001%). This missense change has been observed in individuals with hemophilia B (PMID: 1615486, 2752109, 2773937, 19699296, 22544209, 22639855). This variant is also known as p.Arg145His. ClinVar contains an entry for this variant (Variation ID: 10585). 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 with a negative predictive value of 80%. This variant disrupts the p.Arg191 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. For these reasons, this variant has been classified as Pathogenic. -

Thrombophilia, X-linked, due to factor 9 defect

Pathogenic:1

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Jun 18, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3, PS4_Moderate, PM1, PM2 -

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

0.16

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;.

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

4.3

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.2

N;N

REVEL

Pathogenic

0.73

Sift

Benign

0.038

D;D

Sift4G

Uncertain

0.059

T;T

Polyphen

0.46

P;.

Vest4

0.46

MutPred

0.86

Gain of methylation at K188 (P = 0.0471);.;

MVP

1.0

MPC

1.8

ClinPred

0.75

GERP RS

4.9

Varity_R

0.43

gMVP

0.98

Mutation Taster

=29/71

disease causing (ClinVar)

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over