X-139530771-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000133.4(F9):c.7C>T(p.Arg3Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000024 in 1,207,866 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000023 ( 0 hom. 7 hem. )

Consequence

F9
NM_000133.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.382

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012279302).

BP6

Variant X-139530771-C-T is Benign according to our data. Variant chrX-139530771-C-T is described in ClinVar as [Benign]. Clinvar id is 765903.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000356 (4/112423) while in subpopulation EAS AF= 0.000842 (3/3563). AF 95% confidence interval is 0.000229. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Hemizygotes in GnomAdExome4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4 link	c.7C>T	p.Arg3Cys	missense_variant	Exon 1 of 8	ENST00000218099.7	NP_000124.1	P00740-1
F9	NM_001313913.2 link	c.7C>T	p.Arg3Cys	missense_variant	Exon 1 of 7		NP_001300842.1	P00740-2
F9	XM_005262397.5 link	c.7C>T	p.Arg3Cys	missense_variant	Exon 1 of 7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
F9	ENST00000218099.7 link	c.7C>T	p.Arg3Cys	missense_variant	Exon 1 of 8	1	NM_000133.4	ENSP00000218099.2	P00740-1
F9	ENST00000394090.2 link	c.7C>T	p.Arg3Cys	missense_variant	Exon 1 of 7	1		ENSP00000377650.2	P00740-2
F9	ENST00000479617.2 link	n.14C>T		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.0000356

AC:

AN:

112367

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34531

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000946

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000839

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000874

AC:

AN:

183021

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

67635

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000650

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000490

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000228

AC:

AN:

1095443

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

361019

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000853

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000364

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000107

Gnomad4 OTH exome

AF:

0.0000435

GnomAD4 genome

AF:

0.0000356

AC:

AN:

112423

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34597

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000945

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000842

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary factor IX deficiency disease

Benign:1

Jan 02, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.54

CADD

Benign

6.3

DANN

Benign

0.80

DEOGEN2

Benign

0.29

T;.

FATHMM_MKL

Benign

0.0041

LIST_S2

Benign

0.59

T;T

M_CAP

Benign

0.082

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

-0.49

N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.27

N;N

REVEL

Benign

0.16

Sift

Benign

0.23

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.0

B;.

Vest4

0.13

MutPred

0.40

Gain of catalytic residue at M1 (P = 2e-04);Gain of catalytic residue at M1 (P = 2e-04);

MVP

0.37

MPC

0.099

ClinPred

0.010

GERP RS

-1.1

Varity_R

0.068

gMVP

0.75

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