X-139561710-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000133.4(F9):c.1025C>T(p.Thr342Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,098,006 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. T342K) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

F9
NM_000133.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:13

Conservation

PhyloP100: 3.72

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 16 ACMG points.

PM1

In a chain Coagulation factor IXa heavy chain (size 234) in uniprot entity FA9_HUMAN there are 51 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.933

PP5

Variant X-139561710-C-T is Pathogenic according to our data. Variant chrX-139561710-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10607.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4 link	c.1025C>T	p.Thr342Met	missense_variant	Exon 8 of 8	ENST00000218099.7	NP_000124.1	P00740-1
F9	NM_001313913.2 link	c.911C>T	p.Thr304Met	missense_variant	Exon 7 of 7		NP_001300842.1	P00740-2
F9	XM_005262397.5 link	c.896C>T	p.Thr299Met	missense_variant	Exon 7 of 7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
F9	ENST00000218099.7 link	c.1025C>T	p.Thr342Met	missense_variant	Exon 8 of 8	1	NM_000133.4	ENSP00000218099.2	P00740-1
F9	ENST00000394090.2 link	c.911C>T	p.Thr304Met	missense_variant	Exon 7 of 7	1		ENSP00000377650.2	P00740-2
F9	ENST00000643157.1 link	n.1692C>T		non_coding_transcript_exon_variant	Exon 6 of 7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1098006

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363372

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:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary factor IX deficiency disease

Pathogenic:7

Feb 09, 2024

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1025C>T; p.Thr342Met variant is completely absent from gnomAD v2.1.1 and v3.1.1. This missense variant has a REVEL score of 0.799 and meets PP3 criteria (threshold >0.6). There are over 100 patients are reported in the literature with mild to severe hemophilia B and this variant, meeting F9 phenotype criteria for PP4_Moderate and PS4_Very strong (PMID: 29296726, 8314564). 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. -

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.1025C>T(p.Thr342Met) in F9 gene has been reported previously in multiple individuals with Hemophilia B (Li T, et al., 2014). The other variants at this codon (c.1024A>G; p.Thr342Ala, c.1024A>C; p.Thr342Arg, c.1025C>A; p.Thr342Lys) have been described in individuals affected with hemophilia B and are considered pathogenic (Turro E, et al., 2020). The c.1025C>T variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic/ Pathogenic (multiple submissions). The amino acid Threonine at position 342 is changed to a Methionine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Thr342Met in F9 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Nov 25, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 17, 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.1025C>T (p.Thr342Met) results in a non-conservative amino acid change located in the trypsin domain (IPR001254) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183381 control chromosomes (gnomAD). c.1025C>T has been reported in the literature in numerous individuals affected with Factor IX Deficiency (Hemophilia B) (e.g., Ketterling_1991, Miller_2012, Hamasaki-Katagiri_2012). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22639855, 1864609, 22103590). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Aug 17, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F9 c.1025C>T; p.Thr342Met variant (rs137852254), also known as Thr296Met, has been described in the literature in individuals with variable hemophilia B severity (see link to F9 database and references therein, Bicocchi 2006, Ketterline 1991, Radic 2013, Sharathkumar 2009). The variant is listed is also reported in ClinVar (Variation ID: 10607), and is absent from general population databases (Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The threonine at codon 342 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.799). Additionally, other variants at this codon (c.1024A>G; p.Thr342Ala, c.1024A>C; p.Thr342Arg, c.1025C>A; p.Thr342Lys) have been described in individuals affected with hemophilia B and are considered pathogenic (see link to F9 database and references therein). Based on available information, the p.Thr342Met variant is considered pathogenic for hemophilia B with variable outcomes. REFERENCES Link to F9 database: http://www.factorix.org/ Bicocchi MP et al. Insight into molecular changes of the FIX protein in a series of Italian patients with haemophilia B. Haemophilia. 2006 12(3):263-70. Ketterling RP et al. T296----M, a common mutation causing mild hemophilia B in the Amish and others: founder effect, variability in factor IX activity assays, and rapid carrier detection. Hum Genet. 1991 87(3):333-7. Radic CP et al. Assessment of the F9 genotype-specific FIX inhibitor risks and characterisation of 10 novel severe F9 defects in the first molecular series of Argentinian patients with haemophilia B. Thromb Haemost. 2013 109(1):24-33. Sharathkumar A et al. Variability in bleeding phenotype in Amish carriers of haemophilia B with the 31008 C-->T mutation. Haemophilia. 2009 15(1):91-100. -

Sep 02, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP5, PM2, PM5, PS4_moderate -

F9-related disorder

Pathogenic:1

Aug 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The F9 c.1025C>T variant is predicted to result in the amino acid substitution p.Thr342Met. This variant, also referred to as p.Thr296Met using legacy nomenclature, has been reported in many individuals with mild to severe forms of hemophilia B (Green et al. 1990. PubMed ID: 1972560; see ID number 98 in Belvini et al. 2005. PubMed ID: 15921378; Factor IX Gene (F9) Variant Database: http://www.factorix.org/). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

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

Pathogenic:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 342 of the F9 protein (p.Thr342Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hemophilia B (PMID: 1864609, 2066105, 22639855). It is commonly reported in individuals of Amish ancestry (PMID: 1864609, 2066105, 22639855). This variant is also known as Thr296Met. ClinVar contains an entry for this variant (Variation ID: 10607). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt F9 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

Apr 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: 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: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.74

T;T

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

1.7

L;.

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.0

D;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.42

MutPred

0.88

Gain of phosphorylation at Y341 (P = 0.1121);.;

MVP

0.99

MPC

1.7

ClinPred

0.99

GERP RS

5.7

Varity_R

0.72

gMVP

0.97

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