chrX-139530783-A-T

Position:

chrX-139530783-A-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
F9	NM_000133.4 linkuse as main transcript	c.19A>T	p.Ile7Phe	missense_variant	1/8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2 linkuse as main transcript	c.19A>T	p.Ile7Phe	missense_variant	1/7		NP_001300842.1
F9	XM_005262397.5 linkuse as main transcript	c.19A>T	p.Ile7Phe	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.19A>T	p.Ile7Phe	missense_variant	1/8	1	NM_000133.4	ENSP00000218099	P1	P00740-1
F9	ENST00000394090.2 linkuse as main transcript	c.19A>T	p.Ile7Phe	missense_variant	1/7	1		ENSP00000377650		P00740-2
F9	ENST00000479617.2 linkuse as main transcript	n.26A>T		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes

AF:

0.000889

AC:

100

AN:

112507

Hom.:

Cov.:

AF XY:

0.000808

AC XY:

AN XY:

34659

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

GnomAD3 exomes

AF:

0.000918

AC:

168

AN:

183102

Hom.:

AF XY:

0.000842

AC XY:

AN XY:

67692

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 SAS 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

Gnomad4 AFR exome

AF:

0.000190

Gnomad4 AMR exome

AF:

0.000540

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000469

Gnomad4 NFE exome

AF:

0.00160

Gnomad4 OTH exome

AF:

0.000955

GnomAD4 genome

AF:

0.000888

AC:

100

AN:

112563

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

34725

show subpopulations

Gnomad4 AFR

AF:

0.000161

Gnomad4 AMR

AF:

0.0000943

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000323

Gnomad4 NFE

AF:

0.00169

Gnomad4 OTH

AF:

0.00130

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

Significance: Benign

Submissions summary: Uncertain:1Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary factor IX deficiency disease

Uncertain:1Benign:4

Uncertain significance, no assertion criteria provided	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, reviewed by expert panel	curation	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	Feb 09, 2024	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. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 08, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

F9-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 21, 2022

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 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

F9: BS1, BS2 -

FACTOR IX POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Sep 01, 1989

- -

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 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.33

T;.

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.76

T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.026

T;T

MetaSVM

Uncertain

-0.28

MutationAssessor

Uncertain

2.1

M;M

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.35

N;N

REVEL

Uncertain

0.58

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.056

T;D

Polyphen

0.0030

B;.

Vest4

0.49

MVP

1.0

MPC

0.15

ClinPred

0.029

GERP RS

2.0

Varity_R

0.098

gMVP

0.78

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