Genetic Variant F9:p.Arg3Cys (chrX-139530771-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 1P and 14B. PP2BP4_StrongBP6_ModerateBS1BS2

The NM_000133.4(F9):c.7C>T(p.Arg3Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000024 in 1,207,866 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000023 ( 0 hom. 7 hem. )

Consequence

F9
NM_000133.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.382

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 -13 ACMG points.

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=0.012279302).

BP6

Variant X-139530771-C-T is Benign according to our data. Variant chrX-139530771-C-T is described in ClinVar as Benign. ClinVar VariationId is 765903.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000356 (4/112423) while in subpopulation EAS AF = 0.000842 (3/3563). AF 95% confidence interval is 0.000229. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 7 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.7C>T	p.Arg3Cys	missense	Exon 1 of 8	NP_000124.1	P00740-1
	F9	NM_001313913.2		c.7C>T	p.Arg3Cys	missense	Exon 1 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.7C>T	p.Arg3Cys	missense	Exon 1 of 8	ENSP00000218099.2	P00740-1
F9	ENST00000394090.2	TSL:1	c.7C>T	p.Arg3Cys	missense	Exon 1 of 7	ENSP00000377650.2	P00740-2
F9	ENST00000479617.2	TSL:5	n.14C>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes

AF:

0.0000356

AC:

AN:

112367

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000946

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000839

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:

0.0000874

AC:

AN:

183021

AF XY:

0.0000444

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000650

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000490

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000228

AC:

AN:

1095443

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

361019

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26352

American (AMR)

AF:

0.0000853

AC:

AN:

35183

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19348

East Asian (EAS)

AF:

0.000364

AC:

AN:

30194

South Asian (SAS)

AF:

0.00

AC:

AN:

54072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40503

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.0000107

AC:

AN:

839662

Other (OTH)

AF:

0.0000435

AC:

AN:

45998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0000356

AC:

AN:

112423

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34597

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31036

American (AMR)

AF:

0.0000945

AC:

AN:

10586

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.000842

AC:

AN:

3563

South Asian (SAS)

AF:

0.00

AC:

AN:

2709

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53276

Other (OTH)

AF:

0.00

AC:

AN:

1534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

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:

0.00

Hom.:

ExAC

AF:

0.000124

AC:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary factor IX deficiency disease (1)

Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.54

CADD

Benign

6.3

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.29

FATHMM_MKL

Benign

0.0041

LIST_S2

Benign

0.59

M_CAP

Benign

0.082

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.58

MutationAssessor

Benign

-0.49

PhyloP100

-0.38

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.27

REVEL

Benign

0.16

Sift

Benign

0.23

Sift4G

Benign

0.20

Polyphen

0.0

Vest4

0.13

MutPred

0.40

Gain of catalytic residue at M1 (P = 2e-04)

MVP

0.37

MPC

0.099

ClinPred

0.010

GERP RS

-1.1

PromoterAI

0.0010

Neutral

(source)

Varity_R

0.068

gMVP

0.75

Mutation Taster

=100/0

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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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