rs137852242

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 4P and 7B. PM1PM5BP4BP6_ModerateBS2

The NM_000133.4(F9):c.679G>A(p.Val227Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,098,112 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 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 Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V227D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.000014 ( 0 hom. 5 hem. )

Consequence

F9
NM_000133.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.416

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 -3 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000133.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

BP4

Computational evidence support a benign effect (MetaRNN=0.39294234).

BP6

Variant X-139551220-G-A is Benign according to our data. Variant chrX-139551220-G-A is described in ClinVar as [Benign]. Clinvar id is 1596936.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
F9	NM_000133.4 linkuse as main transcript	c.679G>A	p.Val227Ile	missense_variant	6/8	ENST00000218099.7
F9	NM_001313913.2 linkuse as main transcript	c.565G>A	p.Val189Ile	missense_variant	5/7
F9	XM_005262397.5 linkuse as main transcript	c.550G>A	p.Val184Ile	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F9	ENST00000218099.7 linkuse as main transcript	c.679G>A	p.Val227Ile	missense_variant	6/8	1	NM_000133.4	P1	P00740-1
F9	ENST00000394090.2 linkuse as main transcript	c.565G>A	p.Val189Ile	missense_variant	5/7	1			P00740-2
F9	ENST00000643157.1 linkuse as main transcript	n.1346G>A		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000654

AC:

AN:

183459

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

67917

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.000147

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1098112

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363468

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:

0.0000166

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 02, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.19

DANN

Benign

0.25

DEOGEN2

Benign

0.27

T;.

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.73

T;T

M_CAP

Pathogenic

0.62

MetaRNN

Benign

0.39

T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

-0.74

N;.

MutationTaster

Benign

0.66

D;N

PrimateAI

Benign

0.33

PROVEAN

Benign

0.55

N;N

REVEL

Benign

0.26

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.11

MutPred

0.63

Loss of disorder (P = 0.1551);.;

MVP

0.64

MPC

0.56

ClinPred

0.015

GERP RS

0.51

Varity_R

0.15

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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