X-139540095-T-C

Variant names:

• chrX-139540095-T-C
• rs392959
• NM_000133.4:c.278-981T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000133.4(F9):​c.278-981T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.88 (30310 hom., 27886 hem., cov: 22)
  • Failed GnomAD Quality Control
• Consequence: F9 NM_000133.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.84
• 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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4	c.278-981T>C		intron_variant	Intron 3 of 7	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.277+2709T>C		intron_variant	Intron 3 of 6		NP_001300842.1
F9	XM_005262397.5	c.278-981T>C		intron_variant	Intron 3 of 6		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.278-981T>C		intron_variant	Intron 3 of 7	1	NM_000133.4	ENSP00000218099.2
F9	ENST00000394090.2	c.277+2709T>C		intron_variant	Intron 3 of 6	1		ENSP00000377650.2
F9	ENST00000479617.2	n.242-992T>C		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.879 AC: 96335 AN: 109624 Hom.: 30310 Cov.: 22

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.804

Gnomad AMR AF: 0.860

Gnomad ASJ AF: 0.936

Gnomad EAS AF: 0.728

Gnomad SAS AF: 0.770

Gnomad FIN AF: 0.897

Gnomad MID AF: 0.919

Gnomad NFE AF: 0.930

Gnomad OTH AF: 0.883

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.879 AC: 96383 AN: 109672 Hom.: 30310 Cov.: 22 AF XY: 0.873 AC XY: 27886 AN XY: 31936

African (AFR) AF: 0.815 AC: 24583 AN: 30170

American (AMR) AF: 0.859 AC: 8805 AN: 10246

Ashkenazi Jewish (ASJ) AF: 0.936 AC: 2464 AN: 2633

East Asian (EAS) AF: 0.729 AC: 2504 AN: 3434

South Asian (SAS) AF: 0.771 AC: 1927 AN: 2500

European-Finnish (FIN) AF: 0.897 AC: 5124 AN: 5710

Middle Eastern (MID) AF: 0.911 AC: 195 AN: 214

European-Non Finnish (NFE) AF: 0.930 AC: 48924 AN: 52605

Other (OTH) AF: 0.885 AC: 1319 AN: 1491

Alfa AF: 0.913 Hom.: 119106

Bravo AF: 0.872

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.15
DANN	Benign	0.40
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs392959; hg19: chrX-138622254;