chrX-139530790-C-G

Variant names:

• chrX-139530790-C-G
• rs781184105
• NM_000133.4:c.26C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000133.4(F9):​c.26C>G​(p.Ala9Gly) 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 1,096,898 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. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. A9A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.92
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hemophilia B

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• mild hemophilia B

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• moderately severe hemophilia B

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• severe hemophilia B

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• symptomatic form of hemophilia B in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• thrombophilia, X-linked, due to factor 9 defect

  Inheritance: XL Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 162 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 2.1809 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to hemophilia B, symptomatic form of hemophilia B in female carriers, thrombophilia, X-linked, due to factor 9 defect, mild hemophilia B, severe hemophilia B, moderately severe hemophilia B.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31988698).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000133.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F9	NM_000133.4	MANE Select	c.26C>G	p.Ala9Gly	missense	Exon 1 of 8	NP_000124.1	P00740-1
	F9	NM_001313913.2		c.26C>G	p.Ala9Gly	missense	Exon 1 of 7	NP_001300842.1	P00740-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F9	ENST00000218099.7	TSL:1 MANE Select	c.26C>G	p.Ala9Gly	missense	Exon 1 of 8	ENSP00000218099.2	P00740-1
	F9	ENST00000394090.2	TSL:1	c.26C>G	p.Ala9Gly	missense	Exon 1 of 7	ENSP00000377650.2	P00740-2
	F9	ENST00000479617.2	TSL:5	n.33C>G		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.0000218 AC: 4 AN: 183089 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000289

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: 1 AN: 1096898 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362374

African (AFR) AF: 0.00 AC: 0 AN: 26373

American (AMR) AF: 0.00 AC: 0 AN: 35188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19362

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30196

South Asian (SAS) AF: 0.00 AC: 0 AN: 54120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40521

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840954

Other (OTH) AF: 0.00 AC: 0 AN: 46056

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	F9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.9	L
PhyloP100		2.9
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.051	T
Polyphen		0.14	B
Vest4		0.50
MutPred		0.29		Gain of disorder (P = 0.0788)
MVP		0.94
MPC		0.25
ClinPred		0.25	T
GERP RS		5.1
PromoterAI		-0.040	Neutral
Varity_R		0.34
gMVP		0.74
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs781184105; hg19: chrX-138612949;