rs6048

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BP4

This summary comes from the ClinGen Evidence Repository: The c.580A>G (p.Thr194Ala) variant is reported at an MAF of 0.3026 (27985/92495 alleles) in the non-Finnish European population in gnomAD v2.1.1 with 2609 homozygotes and 10667 hemizygotes, meeting BA1 criteria of MAF > 0.0000556. Note that gnomAD v3.1.1 reports a frequency of 0.3041 in the NFE population, with 1859 homozygotes and 4024 hemizygotes. This missense variant has a REVEL score of 0.255 (<0.3) and SpliceAI predicts no impact on splicing, with a score of 0.0, meeting BP4 criteria. 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, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA121125/MONDO:0010604/080

Frequency

Genomes: 𝑓 0.22 ( 2307 hom., 7148 hem., cov: 23)

Exomes 𝑓: 0.27 ( 29445 hom. 98085 hem. )

Consequence

F9
NM_000133.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:11

Conservation

PhyloP100: 0.555

Publications

36 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 -9 ACMG points.

BP4

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

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4 link	c.580A>G	p.Thr194Ala	missense_variant	Exon 6 of 8	ENST00000218099.7	NP_000124.1	P00740-1
F9	NM_001313913.2 link	c.466A>G	p.Thr156Ala	missense_variant	Exon 5 of 7		NP_001300842.1	P00740-2
F9	XM_005262397.5 link	c.451A>G	p.Thr151Ala	missense_variant	Exon 5 of 7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
F9	ENST00000218099.7 link	c.580A>G	p.Thr194Ala	missense_variant	Exon 6 of 8	1	NM_000133.4	ENSP00000218099.2	P00740-1
F9	ENST00000394090.2 link	c.466A>G	p.Thr156Ala	missense_variant	Exon 5 of 7	1		ENSP00000377650.2	P00740-2
F9	ENST00000643157.1 link	n.1247A>G		non_coding_transcript_exon_variant	Exon 4 of 7

Frequencies

GnomAD3 genomes

AF:

0.223

AC:

24831

AN:

111270

Hom.:

2310

Cov.:

show subpopulations

Gnomad AFR

AF:

0.132

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.149

Gnomad ASJ

AF:

0.231

Gnomad EAS

AF:

0.00392

Gnomad SAS

AF:

0.162

Gnomad FIN

AF:

0.262

Gnomad MID

AF:

0.285

Gnomad NFE

AF:

0.304

Gnomad OTH

AF:

0.184

GnomAD2 exomes

AF:

0.217

AC:

39784

AN:

183245

AF XY:

0.225

show subpopulations

Gnomad AFR exome

AF:

0.132

Gnomad AMR exome

AF:

0.101

Gnomad ASJ exome

AF:

0.238

Gnomad EAS exome

AF:

0.00253

Gnomad FIN exome

AF:

0.266

Gnomad NFE exome

AF:

0.303

Gnomad OTH exome

AF:

0.242

GnomAD4 exome

AF:

0.273

AC:

299272

AN:

1097623

Hom.:

29445

Cov.:

AF XY:

0.270

AC XY:

98085

AN XY:

363129

show subpopulations

African (AFR)

AF:

0.126

AC:

3318

AN:

26399

American (AMR)

AF:

0.108

AC:

3789

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.240

AC:

4643

AN:

19384

East Asian (EAS)

AF:

0.00136

AC:

AN:

30206

South Asian (SAS)

AF:

0.177

AC:

9591

AN:

54133

European-Finnish (FIN)

AF:

0.271

AC:

10969

AN:

40525

Middle Eastern (MID)

AF:

0.275

AC:

1137

AN:

4132

European-Non Finnish (NFE)

AF:

0.302

AC:

254229

AN:

841577

Other (OTH)

AF:

0.251

AC:

11555

AN:

46065

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

7860

15720

23579

31439

39299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8664

17328

25992

34656

43320

<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:

0.223

AC:

24829

AN:

111325

Hom.:

2307

Cov.:

AF XY:

0.213

AC XY:

7148

AN XY:

33559

show subpopulations

African (AFR)

AF:

0.132

AC:

4053

AN:

30725

American (AMR)

AF:

0.148

AC:

1560

AN:

10507

Ashkenazi Jewish (ASJ)

AF:

0.231

AC:

611

AN:

2647

East Asian (EAS)

AF:

0.00422

AC:

AN:

3556

South Asian (SAS)

AF:

0.164

AC:

433

AN:

2643

European-Finnish (FIN)

AF:

0.262

AC:

1552

AN:

5918

Middle Eastern (MID)

AF:

0.266

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.304

AC:

16091

AN:

52916

Other (OTH)

AF:

0.181

AC:

275

AN:

1519

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

698

1397

2095

2794

3492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

258

516

774

1032

1290

<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:

0.268

Hom.:

30725

Bravo

AF:

0.207

TwinsUK

AF:

0.299

AC:

1107

ALSPAC

AF:

0.300

AC:

867

ESP6500AA

AF:

0.124

AC:

474

ESP6500EA

AF:

0.298

AC:

2007

ExAC

AF:

0.224

AC:

27172

EpiCase

AF:

0.293

EpiControl

AF:

0.302

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary factor IX deficiency disease

Benign:4

Feb 09, 2024

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.580A>G (p.Thr194Ala) variant is reported at an MAF of 0.3026 (27985/92495 alleles) in the non-Finnish European population in gnomAD v2.1.1 with 2609 homozygotes and 10667 hemizygotes, meeting BA1 criteria of MAF > 0.0000556. Note that gnomAD v3.1.1 reports a frequency of 0.3041 in the NFE population, with 1859 homozygotes and 4024 hemizygotes. This missense variant has a REVEL score of 0.255 (<0.3) and SpliceAI predicts no impact on splicing, with a score of 0.0, meeting BP4 criteria. 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, BP4. -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Feb 12, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 25, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Deep venous thrombosis, protection against

Benign:1

May 01, 2009

OMIM

Significance:protective

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Thrombophilia, X-linked, due to factor 9 defect

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

0.53

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.38

T;.

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.32

T;T

MetaRNN

Benign

0.0050

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;.

PhyloP100

0.56

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.92

N;N

REVEL

Benign

0.26

Sift

Benign

0.65

T;T

Sift4G

Benign

0.74

T;T

Polyphen

0.0

B;.

Vest4

0.064

MPC

0.62

ClinPred

0.0019

GERP RS

1.2

Varity_R

0.059

gMVP

0.93

Mutation Taster

=89/11

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over