rs137852275

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_000133.4(F9):c.1070G>A(p.Gly357Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G357R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 22)

Consequence

F9
NM_000133.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.57

Publications

5 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 13 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain 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 chrX-139561754-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 162 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 2.1809 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to hemophilia B, symptomatic form of hemophilia B in female carriers, thrombophilia, X-linked, due to factor 9 defect, mild hemophilia B, severe hemophilia B, moderately severe hemophilia B.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant X-139561755-G-A is Pathogenic according to our data. Variant chrX-139561755-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10647.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
F9	NM_000133.4 link	c.1070G>A	p.Gly357Glu	missense_variant	Exon 8 of 8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2 link	c.956G>A	p.Gly319Glu	missense_variant	Exon 7 of 7		NP_001300842.1
F9	XM_005262397.5 link	c.941G>A	p.Gly314Glu	missense_variant	Exon 7 of 7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
F9	ENST00000218099.7 link	c.1070G>A	p.Gly357Glu	missense_variant	Exon 8 of 8	1	NM_000133.4	ENSP00000218099.2
F9	ENST00000394090.2 link	c.956G>A	p.Gly319Glu	missense_variant	Exon 7 of 7	1		ENSP00000377650.2
F9	ENST00000643157.1 link	n.1723+14G>A		intron_variant	Intron 6 of 6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary factor IX deficiency disease

Pathogenic:1

Nov 26, 1991

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Aug 08, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The F9 c.1070G>A; p.Gly357Glu variant (rs137852275), also known as 31053G>A, p.Gly311Glu or factor IX Amagasaki, is reported in the literature in multiple individuals affected with moderate to severe hemophilia A (Chavali 2009, Giannelli 1994, Hamasaki-Katagiri 2012, see link to FIX database and references therein). This variant is reported in ClinVar (Variation ID: 10647), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 357 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional assays show a complete loss of coagulant and esterase activities (Miyata 1991). Additionally, other amino acid substitutions at this codon (c.1069G>A; p.Gly357Arg, c.1070G>T; p.Gly357Val) have been reported in individuals with hemophilia B and are considered pathogenic (Chavali 2009, Giannelli 1994, Hamasaki-Katagiri 2012, FIX database and references therein). Based on available information, this variant is considered to be pathogenic. References: Link to FIX 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. Giannelli F et al. Haemophilia B: database of point mutations and short additions and deletions, fifth edition, 1994. Nucleic Acids Res. 1994 Sep;22(17):3534-46. 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. Miyata T et al. Factor IX Amagasaki: a new mutation in the catalytic domain resulting in the loss of both coagulant and esterase activities. Biochemistry. 1991 Nov 26;30(47):11286-91. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.73

BayesDel_noAF

Pathogenic

0.80

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;.

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.89

D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

1.0

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

H;.

PhyloP100

9.6

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-8.0

D;D

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.94

MutPred

0.99

Loss of MoRF binding (P = 0.036);.;

MVP

1.0

MPC

1.9

ClinPred

1.0

GERP RS

5.7

Varity_R

0.99

gMVP

1.0

Mutation Taster

=1/99

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over