rs387906480

Variant names:

• chrX-139530795-T-A
• rs387906480
• NM_000133.4:c.31T>A
• F9 p.Ser11Thr

Your query was ambiguous. Multiple possible variants found:

• chrX-139530795-T-A
• chrX-139530795-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_000133.4(F9):​c.31T>A​(p.Ser11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 112,452 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene F9 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: -0.482
• Publications: 1 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

Specifications for F9 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 3 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 symptomatic form of hemophilia B in female carriers, severe hemophilia B, thrombophilia, X-linked, due to factor 9 defect, hemophilia B, mild hemophilia B, moderately severe hemophilia B.
• PP5: Variant X-139530795-T-A is Pathogenic according to our data. Variant chrX-139530795-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 10656.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.102716416). . Strength limited to SUPPORTING due to the PP5.

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.31T>A	p.Ser11Thr	missense	Exon 1 of 8	NP_000124.1	P00740-1
	F9	NM_001313913.2		c.31T>A	p.Ser11Thr	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.31T>A	p.Ser11Thr	missense	Exon 1 of 8	ENSP00000218099.2	P00740-1
	F9	ENST00000394090.2	TSL:1	c.31T>A	p.Ser11Thr	missense	Exon 1 of 7	ENSP00000377650.2	P00740-2
	F9	ENST00000479617.2	TSL:5	n.38T>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.00000889 AC: 1 AN: 112452 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000889 AC: 1 AN: 112452 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34616

African (AFR) AF: 0.0000323 AC: 1 AN: 30982

American (AMR) AF: 0.00 AC: 0 AN: 10584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3583

South Asian (SAS) AF: 0.00 AC: 0 AN: 2717

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6185

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53307

Other (OTH) AF: 0.00 AC: 0 AN: 1511

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	1	-	Hereditary factor IX deficiency disease (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	3.8
DANN	Benign	0.56
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-0.48
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.21
Sift	Benign	0.50	T
Sift4G	Benign	0.69	T
PromoterAI		0.017	Neutral
Varity_R		0.083
gMVP		0.62
Mutation Taster		=20/80	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs387906480;

hg19: chrX-138612954;