rs4149755

Variant names:

• chrX-139541953-T-A
• rs4149755
• NM_000133.4:c.391+764T>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.391+764T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0431 in 111,569 control chromosomes in the GnomAD database, including 128 homozygotes. There are 1,369 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 0.043 (128 hom., 1369 hem., cov: 23)
• Consequence: F9 NM_000133.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.765
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4	c.391+764T>A		intron_variant	Intron 4 of 7	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.277+4567T>A		intron_variant	Intron 3 of 6		NP_001300842.1
F9	XM_005262397.5	c.391+764T>A		intron_variant	Intron 4 of 6		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.391+764T>A		intron_variant	Intron 4 of 7	1	NM_000133.4	ENSP00000218099.2
F9	ENST00000394090.2	c.277+4567T>A		intron_variant	Intron 3 of 6	1		ENSP00000377650.2
F9	ENST00000479617.2	n.344+764T>A		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes AF: 0.0431 AC: 4805 AN: 111516 Hom.: 128 Cov.: 23

Gnomad AFR AF: 0.00862

Gnomad AMI AF: 0.0292

Gnomad AMR AF: 0.0360

Gnomad ASJ AF: 0.0241

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00598

Gnomad FIN AF: 0.0701

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0676

Gnomad OTH AF: 0.0393

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

GnomAD4 genome AF: 0.0431 AC: 4805 AN: 111569 Hom.: 128 Cov.: 23 AF XY: 0.0405 AC XY: 1369 AN XY: 33813

African (AFR) AF: 0.00860 AC: 265 AN: 30797

American (AMR) AF: 0.0359 AC: 376 AN: 10459

Ashkenazi Jewish (ASJ) AF: 0.0241 AC: 64 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3540

South Asian (SAS) AF: 0.00562 AC: 15 AN: 2667

European-Finnish (FIN) AF: 0.0701 AC: 422 AN: 6016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0676 AC: 3584 AN: 53016

Other (OTH) AF: 0.0388 AC: 59 AN: 1519

Alfa AF: 0.0590 Hom.: 351

Bravo AF: 0.0396

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.6
DANN	Benign	0.63
PhyloP100		0.77
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: rs4149755; hg19: chrX-138624112;