chrX-139560786-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.769G>A variant in F9 is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 257 (p.Val257Ile). The highest population minor allele frequency in gnomAD v2.1.1 is 0.001548 (23/14862 alleles) in the East Asian population a grpmax FAF for exomes = 0.001015 and genomes = 0.0003535, which is higher than the ClinGen Coagulation Factor Deficiency VCEP threshold (>=0.0000556) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for Hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP for F9 (version 1.0.0, released 10/5/2023): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10529834/MONDO:0010604/080

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.00020 ( 1 hom. 83 hem. )

Consequence

F9
NM_000133.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.992

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

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.769G>A	p.Val257Ile	missense_variant	Exon 7 of 8	ENST00000218099.7	NP_000124.1	P00740-1
F9	NM_001313913.2 link	c.655G>A	p.Val219Ile	missense_variant	Exon 6 of 7		NP_001300842.1	P00740-2
F9	XM_005262397.5 link	c.640G>A	p.Val214Ile	missense_variant	Exon 6 of 7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
F9	ENST00000218099.7 link	c.769G>A	p.Val257Ile	missense_variant	Exon 7 of 8	1	NM_000133.4	ENSP00000218099.2	P00740-1
F9	ENST00000394090.2 link	c.655G>A	p.Val219Ile	missense_variant	Exon 6 of 7	1		ENSP00000377650.2	P00740-2
F9	ENST00000643157.1 link	n.1436G>A		non_coding_transcript_exon_variant	Exon 5 of 7

Frequencies

GnomAD3 genomes

AF:

0.000107

AC:

AN:

111714

Hom.:

Cov.:

AF XY:

0.0000590

AC XY:

AN XY:

33896

show subpopulations

Gnomad AFR

AF:

0.000163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000951

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00112

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000167

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000664

GnomAD3 exomes

AF:

0.000125

AC:

AN:

183446

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

67892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00152

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000200

AC:

219

AN:

1097324

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

362734

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00659

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000741

Gnomad4 NFE exome

AF:

0.00000951

Gnomad4 OTH exome

AF:

0.000109

GnomAD4 genome

AF:

0.000107

AC:

AN:

111765

Hom.:

Cov.:

AF XY:

0.0000589

AC XY:

AN XY:

33957

show subpopulations

Gnomad4 AFR

AF:

0.000162

Gnomad4 AMR

AF:

0.0000950

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00112

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000167

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000656

Alfa

AF:

0.000183

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary factor IX deficiency disease

Uncertain:1Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

Jan 07, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

F9-related disorder

Benign:1

Jan 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Aug 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

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

0.060

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.20

CADD

Benign

0.0030

DANN

Benign

0.61

DEOGEN2

Benign

0.39

T;.

FATHMM_MKL

Benign

0.0087

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.069

MetaRNN

Benign

0.026

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

-1.1

N;.

PrimateAI

Benign

0.25

PROVEAN

Benign

0.81

N;N

REVEL

Uncertain

0.48

Sift

Benign

0.49

T;T

Sift4G

Benign

0.41

T;T

Polyphen

0.0

B;.

Vest4

0.40

MVP

0.98

MPC

0.52

ClinPred

0.020

GERP RS

-5.8

Varity_R

0.051

gMVP

0.90

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over