chrX-139530772-G-A

Position:

chrX-139530772-G-A

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.8G>A (p.Arg3His) variant is reported at an MAF of 0.001469 (28/19065 alleles) in the African/African American population in gnomAD v2.1.1 with 8 hemizygotes, meeting BA1 criteria of MAF > 0.0000556. gnomAD v3.1.1 reports 13 hemizygotes. REVEL score does not meet thresholds 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/CA10529706/MONDO:0010604/080

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., 13 hem., cov: 24)

Exomes 𝑓: 0.00013 ( 2 hom. 46 hem. )

Consequence

F9
NM_000133.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:7

Conservation

PhyloP100: 0.553

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:

Genome browser will be placed here

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/exons	MANE	Protein
F9	NM_000133.4 linkuse as main transcript	c.8G>A	p.Arg3His	missense_variant	1/8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2 linkuse as main transcript	c.8G>A	p.Arg3His	missense_variant	1/7		NP_001300842.1
F9	XM_005262397.5 linkuse as main transcript	c.8G>A	p.Arg3His	missense_variant	1/7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7 linkuse as main transcript	c.8G>A	p.Arg3His	missense_variant	1/8	1	NM_000133.4	ENSP00000218099	P1	P00740-1
F9	ENST00000394090.2 linkuse as main transcript	c.8G>A	p.Arg3His	missense_variant	1/7	1		ENSP00000377650		P00740-2
F9	ENST00000479617.2 linkuse as main transcript	n.15G>A		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes

AF:

0.000383

AC:

AN:

112309

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

34477

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000474

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000375

Gnomad OTH

AF:

0.000663

GnomAD3 exomes

AF:

0.000240

AC:

AN:

183043

Hom.:

AF XY:

0.000222

AC XY:

AN XY:

67651

show subpopulations

Gnomad AFR exome

AF:

0.00182

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000361

Gnomad SAS exome

AF:

0.000210

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000129

AC:

141

AN:

1095851

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

361391

show subpopulations

Gnomad4 AFR exome

AF:

0.00159

Gnomad4 AMR exome

AF:

0.000171

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000596

Gnomad4 SAS exome

AF:

0.000388

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000560

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

AF:

0.000392

AC:

AN:

112363

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

34541

show subpopulations

Gnomad4 AFR

AF:

0.00116

Gnomad4 AMR

AF:

0.000473

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.000655

Alfa

AF:

0.000163

Hom.:

Bravo

AF:

0.000544

ESP6500AA

AF:

0.00130

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000264

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary factor IX deficiency disease

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 31, 2019	- -
Benign, reviewed by expert panel	curation	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	Feb 09, 2024	The c.8G>A (p.Arg3His) variant is reported at an MAF of 0.001469 (28/19065 alleles) in the African/African American population in gnomAD v2.1.1 with 8 hemizygotes, meeting BA1 criteria of MAF > 0.0000556. gnomAD v3.1.1 reports 13 hemizygotes. REVEL score does not meet thresholds 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 12, 2022

Variant summary: F9 c.8G>A (p.Arg3His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 183043 control chromosomes including 15 hemizygous males. This frequency is not significantly higher than estimated for a pathogenic variant in F9 causing Factor IX Deficiency (Hemophilia B) (0.00024 vs 0.0065), allowing no conclusion about variant significance. To our knowledge, no penetrant association of c.8G>A in individuals affected with Factor IX Deficiency (Hemophilia B) and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

F9-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2023

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 08, 2021

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Benign

6.0

DANN

Benign

0.44

DEOGEN2

Benign

0.29

T;.

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.59

T;T

M_CAP

Benign

0.063

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.20

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

0.19

N;N

REVEL

Uncertain

0.53

Sift

Benign

0.54

T;T

Sift4G

Benign

0.62

T;T

Polyphen

0.0010

B;.

Vest4

0.091

MVP

0.99

MPC

0.090

ClinPred

0.0022

GERP RS

0.56

Varity_R

0.045

gMVP

0.61

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