NM_000133.4:c.-22T>C

Variant names:

• chrX-139530743-T-C
• NM_000133.4:c.-22T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000133.4(F9):​c.-22T>C variant causes a 5 prime UTR change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: F9 NM_000133.4 5_prime_UTR
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.04
• 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
• PP5: Variant X-139530743-T-C is Pathogenic according to our data. Variant chrX-139530743-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 10644.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37). . 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.-22T>C		5_prime_UTR	Exon 1 of 8	NP_000124.1	P00740-1
	F9	NM_001313913.2		c.-22T>C		5_prime_UTR	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.-22T>C		5_prime_UTR	Exon 1 of 8	ENSP00000218099.2	P00740-1
	F9	ENST00000394090.2	TSL:1	c.-22T>C		upstream_gene	N/A	ENSP00000377650.2	P00740-2
	F9	ENST00000479617.2	TSL:5	n.-15T>C		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1086093 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 352585

African (AFR) AF: 0.00 AC: 0 AN: 26164

American (AMR) AF: 0.00 AC: 0 AN: 35167

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19298

East Asian (EAS) AF: 0.00 AC: 0 AN: 30168

South Asian (SAS) AF: 0.00 AC: 0 AN: 53844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40499

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4103

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 831178

Other (OTH) AF: 0.00 AC: 0 AN: 45672

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hemophilia B leyden (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.59
PhyloP100		4.0
PromoterAI		-0.11	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chrX-138612902;