X-139561500-TA-TAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000133.4(F9):c.839-20dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,186,263 control chromosomes in the GnomAD database, including 74 homozygotes. There are 4,325 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.0078 ( 0 hom., 250 hem., cov: 23)

Exomes 𝑓: 0.012 ( 74 hom. 4075 hem. )

Consequence

F9
NM_000133.4 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.270

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant X-139561500-T-TA is Benign according to our data. Variant chrX-139561500-T-TA is described in ClinVar as Benign. ClinVar VariationId is 255227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00785 (882/112371) while in subpopulation NFE AF = 0.0123 (654/53289). AF 95% confidence interval is 0.0115. There are 0 homozygotes in GnomAd4. There are 250 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 250 XL gene

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.839-20dupA		intron	N/A	NP_000124.1	P00740-1
	F9	NM_001313913.2		c.725-20dupA		intron	N/A	NP_001300842.1	P00740-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
F9	ENST00000218099.7	TSL:1 MANE Select	c.839-24_839-23insA	intron	N/A	ENSP00000218099.2	P00740-1
F9	ENST00000394090.2	TSL:1	c.725-24_725-23insA	intron	N/A	ENSP00000377650.2	P00740-2
F9	ENST00000643157.1		n.1506-24_1506-23insA	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00786

AC:

883

AN:

112313

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.0117

Gnomad AMR

AF:

0.00755

Gnomad ASJ

AF:

0.00754

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00260

Gnomad FIN

AF:

0.00736

Gnomad MID

AF:

0.0126

Gnomad NFE

AF:

0.0123

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00891

AC:

1545

AN:

173494

AF XY:

0.00918

show subpopulations

Gnomad AFR exome

AF:

0.000543

Gnomad AMR exome

AF:

0.00832

Gnomad ASJ exome

AF:

0.00500

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00954

Gnomad NFE exome

AF:

0.0134

Gnomad OTH exome

AF:

0.0117

GnomAD4 exome

AF:

0.0124

AC:

13297

AN:

1073892

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

4075

AN XY:

342576

show subpopulations

African (AFR)

AF:

0.00104

AC:

AN:

25924

American (AMR)

AF:

0.00835

AC:

289

AN:

34595

Ashkenazi Jewish (ASJ)

AF:

0.00612

AC:

116

AN:

18955

East Asian (EAS)

AF:

0.0000333

AC:

AN:

30065

South Asian (SAS)

AF:

0.00316

AC:

165

AN:

52200

European-Finnish (FIN)

AF:

0.00930

AC:

375

AN:

40338

Middle Eastern (MID)

AF:

0.0114

AC:

AN:

4024

European-Non Finnish (NFE)

AF:

0.0143

AC:

11777

AN:

822534

Other (OTH)

AF:

0.0111

AC:

501

AN:

45257

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

463

925

1388

1850

2313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

434

868

1302

1736

2170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00785

AC:

882

AN:

112371

Hom.:

Cov.:

AF XY:

0.00724

AC XY:

250

AN XY:

34541

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

30989

American (AMR)

AF:

0.00754

AC:

AN:

10609

Ashkenazi Jewish (ASJ)

AF:

0.00754

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3587

South Asian (SAS)

AF:

0.00261

AC:

AN:

2686

European-Finnish (FIN)

AF:

0.00736

AC:

AN:

6113

Middle Eastern (MID)

AF:

0.00917

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0123

AC:

654

AN:

53289

Other (OTH)

AF:

0.0104

AC:

AN:

1541

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

109

145

181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00800

Hom.:

Bravo

AF:

0.00797

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.27

BranchPoint Hunter

4.0

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over