X-139530771-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_000133.4(F9):c.7C>A(p.Arg3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,207,811 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

F9
NM_000133.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06267306).

BP6

Variant X-139530771-C-A is Benign according to our data. Variant chrX-139530771-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2929110.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
F9	NM_000133.4 linkuse as main transcript	c.7C>A	p.Arg3Ser	missense_variant	1/8	ENST00000218099.7
F9	NM_001313913.2 linkuse as main transcript	c.7C>A	p.Arg3Ser	missense_variant	1/7
F9	XM_005262397.5 linkuse as main transcript	c.7C>A	p.Arg3Ser	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F9	ENST00000218099.7 linkuse as main transcript	c.7C>A	p.Arg3Ser	missense_variant	1/8	1	NM_000133.4	P1	P00740-1
F9	ENST00000394090.2 linkuse as main transcript	c.7C>A	p.Arg3Ser	missense_variant	1/7	1			P00740-2
F9	ENST00000479617.2 linkuse as main transcript	n.14C>A		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes

AF:

0.00000890

AC:

AN:

112367

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34531

show subpopulations

Gnomad AFR

AF:

0.0000323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183021

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67635

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1095444

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

361018

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000357

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000890

AC:

AN:

112367

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34531

show subpopulations

Gnomad4 AFR

AF:

0.0000323

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jun 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.44

Cadd

Benign

1.2

Dann

Benign

0.65

DEOGEN2

Benign

0.29

T;.

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.47

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.063

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.90

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.050

N;N

REVEL

Benign

0.12

Sift

Benign

0.36

T;T

Sift4G

Benign

0.60

T;T

Polyphen

0.057

B;.

Vest4

0.18

MutPred

0.31

Gain of disorder (P = 0.0702);Gain of disorder (P = 0.0702);

MVP

0.67

MPC

0.088

ClinPred

0.031

GERP RS

-1.1

Varity_R

0.088

gMVP

0.71

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