dbSNP rs1281720529: F9:p.Asn5Lys (chrX-139530779-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000133.4(F9):c.15C>A(p.Asn5Lys) 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 1,096,905 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

F9
NM_000133.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.442

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.117607).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4 link	c.15C>A	p.Asn5Lys	missense_variant	Exon 1 of 8	ENST00000218099.7	NP_000124.1	P00740-1
F9	NM_001313913.2 link	c.15C>A	p.Asn5Lys	missense_variant	Exon 1 of 7		NP_001300842.1	P00740-2
F9	XM_005262397.5 link	c.15C>A	p.Asn5Lys	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.15C>A	p.Asn5Lys	missense_variant	Exon 1 of 8	1	NM_000133.4	ENSP00000218099.2	P00740-1
F9	ENST00000394090.2 link	c.15C>A	p.Asn5Lys	missense_variant	Exon 1 of 7	1		ENSP00000377650.2	P00740-2
F9	ENST00000479617.2 link	n.22C>A		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1096905

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362377

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:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

3.7

DANN

Benign

0.89

DEOGEN2

Benign

0.29

T;.

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.60

T;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.9

M;M

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.20

N;N

REVEL

Benign

0.13

Sift

Benign

0.15

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0

B;.

Vest4

0.22

MutPred

0.29

Gain of ubiquitination at N5 (P = 0.0211);Gain of ubiquitination at N5 (P = 0.0211);

MVP

0.64

MPC

0.084

ClinPred

0.039

GERP RS

-1.8

Varity_R

0.060

gMVP

0.76

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over