rs6049

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.391+7A>G variant is reported at an MAF of 0.1296 (2458/18960 alleles) in the African/African-American population in gnomAD v2.1.1 with 620 hemizygotes and 123 homozygotes, meeting BA1 criteria of MAF > 0.0000556. SpliceAI predicts WT canonical donor loss at -7bp with a delta score of 0.05; however, does not meet criteria for PP3 or BP4. In summary, this 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10529780/MONDO:0010604/080

Frequency

Genomes: 𝑓 0.036 ( 182 hom., 1042 hem., cov: 23)

Exomes 𝑓: 0.0046 ( 230 hom. 1180 hem. )

Consequence

F9
NM_000133.4 splice_region, intron

Scores

Splicing: ADA: 0.00002569

Clinical Significance

Benign reviewed by expert panel B:6

Conservation

PhyloP100: 0.605

Publications

2 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 -8 ACMG points.

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.391+7A>G		splice_region intron	N/A	NP_000124.1	P00740-1
	F9	NM_001313913.2		c.277+3810A>G		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.391+7A>G	splice_region intron	N/A	ENSP00000218099.2	P00740-1
F9	ENST00000394090.2	TSL:1	c.277+3810A>G	intron	N/A	ENSP00000377650.2	P00740-2
F9	ENST00000479617.2	TSL:5	n.344+7A>G	splice_region intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0360

AC:

4020

AN:

111561

Hom.:

181

Cov.:

show subpopulations

Gnomad AFR

AF:

0.124

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000328

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000715

Gnomad OTH

AF:

0.0301

GnomAD2 exomes

AF:

0.0109

AC:

1996

AN:

182372

AF XY:

0.00696

show subpopulations

Gnomad AFR exome

AF:

0.134

Gnomad AMR exome

AF:

0.00538

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000724

Gnomad FIN exome

AF:

0.000944

Gnomad NFE exome

AF:

0.000418

Gnomad OTH exome

AF:

0.00803

GnomAD4 exome

AF:

0.00461

AC:

4679

AN:

1015480

Hom.:

230

Cov.:

AF XY:

0.00398

AC XY:

1180

AN XY:

296634

show subpopulations

African (AFR)

AF:

0.145

AC:

3594

AN:

24761

American (AMR)

AF:

0.00658

AC:

226

AN:

34348

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18017

East Asian (EAS)

AF:

0.00

AC:

AN:

28336

South Asian (SAS)

AF:

0.000383

AC:

AN:

52261

European-Finnish (FIN)

AF:

0.000731

AC:

AN:

38326

Middle Eastern (MID)

AF:

0.0144

AC:

AN:

3824

European-Non Finnish (NFE)

AF:

0.000363

AC:

281

AN:

773042

Other (OTH)

AF:

0.0112

AC:

475

AN:

42565

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

135

269

404

538

673

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<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:

0.0362

AC:

4038

AN:

111614

Hom.:

182

Cov.:

AF XY:

0.0308

AC XY:

1042

AN XY:

33834

show subpopulations

African (AFR)

AF:

0.124

AC:

3813

AN:

30650

American (AMR)

AF:

0.0131

AC:

137

AN:

10481

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3538

South Asian (SAS)

AF:

0.00

AC:

AN:

2643

European-Finnish (FIN)

AF:

0.000328

AC:

AN:

6095

Middle Eastern (MID)

AF:

0.0140

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.000715

AC:

AN:

53154

Other (OTH)

AF:

0.0298

AC:

AN:

1512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

137

274

410

547

684

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0322

Hom.:

143

Bravo

AF:

0.0420

EpiCase

AF:

0.000819

EpiControl

AF:

0.000833

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary factor IX deficiency disease (3)

not provided (2)

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

BayesDel_noAF

Benign

-0.82

CADD

Benign

3.5

(source)

DANN

Benign

0.56

PhyloP100

0.60

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000026

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.050

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