X-139532512-T-C

Variant names:

• chrX-139532512-T-C
• rs401597
• NM_000133.4:c.88+1660T>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.88+1660T>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. The gene F9 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.65 (16829 hom., 20966 hem., cov: 23)
  • Failed GnomAD Quality Control
• Consequence: F9 NM_000133.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.98
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

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.88+1660T>C		intron	N/A	NP_000124.1	P00740-1
	F9	NM_001313913.2		c.88+1660T>C		intron	N/A	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.88+1660T>C		intron	N/A	ENSP00000218099.2	P00740-1
	F9	ENST00000394090.2	TSL:1	c.88+1660T>C		intron	N/A	ENSP00000377650.2	P00740-2
	F9	ENST00000479617.2	TSL:5	n.95+1660T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.646 AC: 71133 AN: 110075 Hom.: 16827 Cov.: 23

Gnomad AFR AF: 0.456

Gnomad AMI AF: 0.535

Gnomad AMR AF: 0.791

Gnomad ASJ AF: 0.746

Gnomad EAS AF: 0.658

Gnomad SAS AF: 0.675

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.660

Gnomad NFE AF: 0.714

Gnomad OTH AF: 0.697

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: 0.646 AC: 71170 AN: 110129 Hom.: 16829 Cov.: 23 AF XY: 0.647 AC XY: 20966 AN XY: 32409

African (AFR) AF: 0.456 AC: 13799 AN: 30268

American (AMR) AF: 0.791 AC: 8141 AN: 10295

Ashkenazi Jewish (ASJ) AF: 0.746 AC: 1951 AN: 2615

East Asian (EAS) AF: 0.657 AC: 2270 AN: 3453

South Asian (SAS) AF: 0.673 AC: 1728 AN: 2566

European-Finnish (FIN) AF: 0.702 AC: 4066 AN: 5796

Middle Eastern (MID) AF: 0.685 AC: 148 AN: 216

European-Non Finnish (NFE) AF: 0.714 AC: 37660 AN: 52752

Other (OTH) AF: 0.700 AC: 1047 AN: 1495

Alfa AF: 0.634 Hom.: 12253

Bravo AF: 0.651

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.023
DANN	Benign	0.47
PhyloP100		-2.0
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

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

Other links and lift over

dbSNP: rs401597;

hg19: chrX-138614671;