X-139551219-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_000133.4(F9):c.678G>T(p.Arg226Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,108 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R226R) has been classified as Likely benign. The gene F9 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

F9
NM_000133.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.339

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

new If you want to explore the variant's impact on the transcript NM_000133.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Specifications for F9 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP7

Synonymous conserved (PhyloP=-0.339 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000133.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F9	NM_000133.4	MANE Select	c.678G>T	p.Arg226Arg	synonymous	Exon 6 of 8	NP_000124.1	P00740-1
	F9	NM_001313913.2		c.564G>T	p.Arg188Arg	synonymous	Exon 5 of 7	NP_001300842.1	P00740-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
F9	ENST00000218099.7	TSL:1 MANE Select	c.678G>T	p.Arg226Arg	synonymous	Exon 6 of 8	ENSP00000218099.2	P00740-1
F9	ENST00000394090.2	TSL:1	c.564G>T	p.Arg188Arg	synonymous	Exon 5 of 7	ENSP00000377650.2	P00740-2
F9	ENST00000643157.1		n.1345G>T		non_coding_transcript_exon	Exon 4 of 7

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111267

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000545

AC:

AN:

183448

AF XY:

0.00

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:

0.0000625

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1098108

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363464

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26400

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.00

AC:

AN:

54147

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841999

Other (OTH)

AF:

0.00

AC:

AN:

46095

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

111267

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33481

African (AFR)

AF:

0.00

AC:

AN:

30560

American (AMR)

AF:

0.00

AC:

AN:

10443

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3538

South Asian (SAS)

AF:

0.00

AC:

AN:

2610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5948

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53107

Other (OTH)

AF:

0.00

AC:

AN:

1495

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.8

(source)

DANN

Benign

0.57

PhyloP100

-0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over