chrX-139530783-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BS2BA1

This summary comes from the ClinGen Evidence Repository: NM_000133.3:c.19A>T variant results in a missense change in the signal peptide. This variant is reported at a frequency of 0.001643 (152/92537 alleles with 57 hemizygotes) in the non-Finnish European population in gnomAD v2.1.1, meeting the BA1 cut-off of >= 0.0000556. At least 2 individuals with the variant and normal FIX levels from the literature and internal laboratory data are reported (PMID:29296726) meeting the BS2 criterion. In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: BA1, BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10529708/MONDO:0010604/080

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., 28 hem., cov: 23)

Exomes 𝑓: 0.0013 ( 2 hom. 461 hem. )

Consequence

F9
NM_000133.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:9

Conservation

PhyloP100: 3.49

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: Benign. The variant received -12 ACMG points.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

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.19A>T	p.Ile7Phe	missense	Exon 1 of 8	NP_000124.1	P00740-1
	F9	NM_001313913.2		c.19A>T	p.Ile7Phe	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.19A>T	p.Ile7Phe	missense	Exon 1 of 8	ENSP00000218099.2	P00740-1
F9	ENST00000394090.2	TSL:1	c.19A>T	p.Ile7Phe	missense	Exon 1 of 7	ENSP00000377650.2	P00740-2
F9	ENST00000479617.2	TSL:5	n.26A>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes

AF:

0.000889

AC:

100

AN:

112507

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000945

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000323

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00169

Gnomad OTH

AF:

0.00132

GnomAD2 exomes

AF:

0.000918

AC:

168

AN:

183102

AF XY:

0.000842

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.000621

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000500

Gnomad NFE exome

AF:

0.00169

Gnomad OTH exome

AF:

0.000885

GnomAD4 exome

AF:

0.00131

AC:

1438

AN:

1097226

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

461

AN XY:

362702

show subpopulations

African (AFR)

AF:

0.000190

AC:

AN:

26378

American (AMR)

AF:

0.000540

AC:

AN:

35189

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19367

East Asian (EAS)

AF:

0.00

AC:

AN:

30200

South Asian (SAS)

AF:

0.00

AC:

AN:

54120

European-Finnish (FIN)

AF:

0.000469

AC:

AN:

40530

Middle Eastern (MID)

AF:

0.000968

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00160

AC:

1347

AN:

841245

Other (OTH)

AF:

0.000955

AC:

AN:

46063

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

140

186

233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.000888

AC:

100

AN:

112563

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

34725

show subpopulations

African (AFR)

AF:

0.000161

AC:

AN:

31061

American (AMR)

AF:

0.0000943

AC:

AN:

10600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3584

South Asian (SAS)

AF:

0.00

AC:

AN:

2713

European-Finnish (FIN)

AF:

0.000323

AC:

AN:

6196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00169

AC:

AN:

53321

Other (OTH)

AF:

0.00130

AC:

AN:

1534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.00159

Hom.:

Bravo

AF:

0.000903

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00138

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00134

AC:

ExAC

AF:

0.000906

AC:

110

EpiCase

AF:

0.00164

EpiControl

AF:

0.00172

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary factor IX deficiency disease (5)

F9 POLYMORPHISM (1)

F9-related disorder (1)

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

Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect;C5393318:Warfarin sensitivity, X-linked (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.33

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.76

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.026

MetaSVM

Uncertain

-0.28

MutationAssessor

Uncertain

2.1

PhyloP100

3.5

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.35

REVEL

Uncertain

0.58

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.056

Polyphen

0.0030

Vest4

0.49

MVP

1.0

MPC

0.15

ClinPred

0.029

GERP RS

2.0

PromoterAI

-0.030

Neutral

(source)

Varity_R

0.098

gMVP

0.78

Mutation Taster

=86/14

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

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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