rs4149754

Variant names:

• chrX-139531533-G-A
• rs4149754
• NM_000133.4:c.88+681G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000133.4(F9):​c.88+681G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0526 in 111,988 control chromosomes in the GnomAD database, including 147 homozygotes. There are 1,738 hemizygotes in GnomAD. 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 0.053 (147 hom., 1738 hem., cov: 23)
• Consequence: F9 NM_000133.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.389
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4	c.88+681G>A		intron_variant	Intron 1 of 7	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.88+681G>A		intron_variant	Intron 1 of 6		NP_001300842.1
F9	XM_005262397.5	c.88+681G>A		intron_variant	Intron 1 of 6		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.88+681G>A		intron_variant	Intron 1 of 7	1	NM_000133.4	ENSP00000218099.2
F9	ENST00000394090.2	c.88+681G>A		intron_variant	Intron 1 of 6	1		ENSP00000377650.2
F9	ENST00000479617.2	n.95+681G>A		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes AF: 0.0526 AC: 5892 AN: 111937 Hom.: 148 Cov.: 23

Gnomad AFR AF: 0.00994

Gnomad AMI AF: 0.0586

Gnomad AMR AF: 0.0379

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.00112

Gnomad SAS AF: 0.0613

Gnomad FIN AF: 0.0672

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0785

Gnomad OTH AF: 0.0475

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

GnomAD4 genome AF: 0.0526 AC: 5886 AN: 111988 Hom.: 147 Cov.: 23 AF XY: 0.0508 AC XY: 1738 AN XY: 34184

African (AFR) AF: 0.00992 AC: 307 AN: 30938

American (AMR) AF: 0.0379 AC: 399 AN: 10538

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 302 AN: 2638

East Asian (EAS) AF: 0.00140 AC: 5 AN: 3570

South Asian (SAS) AF: 0.0619 AC: 167 AN: 2700

European-Finnish (FIN) AF: 0.0672 AC: 407 AN: 6055

Middle Eastern (MID) AF: 0.0868 AC: 19 AN: 219

European-Non Finnish (NFE) AF: 0.0785 AC: 4169 AN: 53112

Other (OTH) AF: 0.0463 AC: 71 AN: 1535

Alfa AF: 0.0682 Hom.: 1675

Bravo AF: 0.0483

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.18
DANN	Benign	0.55
PhyloP100		-0.39
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: rs4149754; hg19: chrX-138613692;