rs137852238

Positions:

chrX-139551113-G-A

Variant summary

Our verdict is Pathogenic. Variant got 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

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 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/exons	MANE	Protein	UniProt
F9	NM_000133.4 link	c.572G>A	p.Arg191His	missense_variant	6/8	ENST00000218099.7	NP_000124.1	P00740-1
F9	NM_001313913.2 link	c.458G>A	p.Arg153His	missense_variant	5/7		NP_001300842.1	P00740-2
F9	XM_005262397.5 link	c.443G>A	p.Arg148His	missense_variant	5/7		XP_005262454.1

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111818

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34006

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

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183455

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67905

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 SAS 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

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:

0.00000356

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111818

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34006

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000944

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

Pathogenic, no assertion criteria provided	clinical testing	Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	Jun 01, 2019	- -
Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 27, 2023	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 15, 1990	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	Feb 09, 2024	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. -

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

Sep 04, 2023

For these reasons, this variant has been classified as Pathogenic. 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. 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: 10585). This variant is also known as p.Arg145His. This missense change has been observed in individuals with hemophilia B (PMID: 1615486, 2752109, 2773937, 19699296, 22544209, 22639855). This variant is present in population databases (rs137852238, gnomAD 0.001%). 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). -

Thrombophilia, X-linked, due to factor 9 defect

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jun 18, 2021

PS3, PS4_Moderate, PM1, PM2 -

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

0.16

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Benign

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;.

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

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