rs137852282

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000133.4(F9):​c.1169T>A​(p.Ile390Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I390F) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

F9
NM_000133.4 missense

Scores

12
4
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.99
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000133.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-139561853-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2632738.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
F9NM_000133.4 linkuse as main transcriptc.1169T>A p.Ile390Asn missense_variant 8/8 ENST00000218099.7
F9NM_001313913.2 linkuse as main transcriptc.1055T>A p.Ile352Asn missense_variant 7/7
F9XM_005262397.5 linkuse as main transcriptc.1040T>A p.Ile347Asn missense_variant 7/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
F9ENST00000218099.7 linkuse as main transcriptc.1169T>A p.Ile390Asn missense_variant 8/81 NM_000133.4 P1P00740-1
F9ENST00000394090.2 linkuse as main transcriptc.1055T>A p.Ile352Asn missense_variant 7/71 P00740-2
F9ENST00000643157.1 linkuse as main transcriptn.1723+113T>A intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
23
Bravo
AF:
0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.90
D;.
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Pathogenic
0.92
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
0.84
D
MutationAssessor
Uncertain
2.7
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-6.7
D;D
REVEL
Pathogenic
0.84
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.90
MutPred
0.98
Loss of catalytic residue at I390 (P = 0.0331);.;
MVP
0.99
MPC
2.2
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.97
gMVP
1.0

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.

Other links and lift over

dbSNP: rs137852282; hg19: chrX-138644013; COSMIC: COSV54381256; API