Variant rs774612303 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_000133.4(F9):c.51C>G(p.Ile17Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,892 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign 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. I17N) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

F9
NM_000133.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.121

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.33785614).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4 link	c.51C>G	p.Ile17Met	missense_variant	Exon 1 of 8	ENST00000218099.7	NP_000124.1	P00740-1
F9	NM_001313913.2 link	c.51C>G	p.Ile17Met	missense_variant	Exon 1 of 7		NP_001300842.1	P00740-2
F9	XM_005262397.5 link	c.51C>G	p.Ile17Met	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.51C>G	p.Ile17Met	missense_variant	Exon 1 of 8	1	NM_000133.4	ENSP00000218099.2	P00740-1
F9	ENST00000394090.2 link	c.51C>G	p.Ile17Met	missense_variant	Exon 1 of 7	1		ENSP00000377650.2	P00740-2
F9	ENST00000479617.2 link	n.58C>G		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183099

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67691

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:

9.12e-7

AC:

AN:

1096892

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362370

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.36

T;.

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.54

T;T

M_CAP

Benign

0.068

MetaRNN

Benign

0.34

T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

1.6

L;L

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.58

N;N

REVEL

Uncertain

0.35

Sift

Benign

0.11

T;D

Sift4G

Benign

0.12

T;T

Polyphen

0.046

B;.

Vest4

0.28

MutPred

0.54

Gain of catalytic residue at I17 (P = 0.0124);Gain of catalytic residue at I17 (P = 0.0124);

MVP

0.93

MPC

0.078

ClinPred

0.029

GERP RS

-1.3

Varity_R

0.13

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over