rs137852236

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 5P and 6B. PM1PM5PP2BP4_ModerateBS2

The NM_000133.4(F9):c.496A>G(p.Asn166Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,096,819 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N166Y) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000017 ( 0 hom. 7 hem. )

Consequence

F9
NM_000133.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.74

Publications

3 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: Likely_benign. The variant received -1 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000133.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-139548467-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 10582.Status of the report is no_assertion_criteria_provided, 0 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.16443467).

BS2

High Hemizygotes in GnomAdExome4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4 link	c.496A>G	p.Asn166Asp	missense_variant	Exon 5 of 8	ENST00000218099.7	NP_000124.1	P00740-1
F9	NM_001313913.2 link	c.382A>G	p.Asn128Asp	missense_variant	Exon 4 of 7		NP_001300842.1	P00740-2
F9	XM_005262397.5 link	c.392-2595A>G		intron_variant	Intron 4 of 6		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
F9	ENST00000218099.7 link	c.496A>G	p.Asn166Asp	missense_variant	Exon 5 of 8	1	NM_000133.4	ENSP00000218099.2	P00740-1
F9	ENST00000394090.2 link	c.382A>G	p.Asn128Asp	missense_variant	Exon 4 of 7	1		ENSP00000377650.2	P00740-2
F9	ENST00000643157.1 link	n.1163A>G		non_coding_transcript_exon_variant	Exon 3 of 7
F9	ENST00000479617.2 link	n.*75A>G		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000173

AC:

AN:

1096819

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

362399

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26360

American (AMR)

AF:

0.00

AC:

AN:

35054

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19338

East Asian (EAS)

AF:

0.00

AC:

AN:

30157

South Asian (SAS)

AF:

0.00

AC:

AN:

53899

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40511

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.0000226

AC:

AN:

841320

Other (OTH)

AF:

0.00

AC:

AN:

46046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

6.6

(source)

DANN

Benign

0.28

DEOGEN2

Benign

0.40

T;.

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.74

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

-1.5

N;.

PhyloP100

1.7

PrimateAI

Benign

0.30

PROVEAN

Benign

2.9

N;N

REVEL

Benign

0.21

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.052

MutPred

0.78

Gain of ubiquitination at K168 (P = 0.0913);.;

MVP

0.76

MPC

0.72

ClinPred

0.027

GERP RS

2.0

Varity_R

0.32

gMVP

0.95

Mutation Taster

=82/18

polymorphism

(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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rs137852236

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over