rs422187

Variant names:

• chrX-139550700-A-C
• rs422187
• NM_000133.4:c.521-362A>C

Your query was ambiguous. Multiple possible variants found:

• chrX-139550700-A-C
• chrX-139550700-A-G

Variant summary

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

The NM_000133.4(F9):​c.521-362A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 110,725 control chromosomes in the GnomAD database, including 5,837 homozygotes. There are 10,784 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. The gene F9 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.35 (5837 hom., 10784 hem., cov: 22)
• Consequence: F9 NM_000133.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.162
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

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.521-362A>C		intron	N/A	NP_000124.1	P00740-1
	F9	NM_001313913.2		c.407-362A>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.521-362A>C		intron	N/A	ENSP00000218099.2	P00740-1
	F9	ENST00000394090.2	TSL:1	c.407-362A>C		intron	N/A	ENSP00000377650.2	P00740-2
	F9	ENST00000643157.1		n.1188-362A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.348 AC: 38544 AN: 110672 Hom.: 5840 Cov.: 22

Gnomad AFR AF: 0.565

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.00420

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.303

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.280

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

GnomAD4 genome AF: 0.348 AC: 38582 AN: 110725 Hom.: 5837 Cov.: 22 AF XY: 0.327 AC XY: 10784 AN XY: 33011

African (AFR) AF: 0.565 AC: 17133 AN: 30310

American (AMR) AF: 0.205 AC: 2148 AN: 10462

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 609 AN: 2635

East Asian (EAS) AF: 0.00450 AC: 16 AN: 3557

South Asian (SAS) AF: 0.166 AC: 440 AN: 2658

European-Finnish (FIN) AF: 0.263 AC: 1525 AN: 5806

Middle Eastern (MID) AF: 0.271 AC: 59 AN: 218

European-Non Finnish (NFE) AF: 0.304 AC: 16052 AN: 52888

Other (OTH) AF: 0.276 AC: 419 AN: 1520

Alfa AF: 0.296 Hom.: 9395

Bravo AF: 0.352

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	4.6
DANN	Benign	0.79
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs422187;

hg19: chrX-138632859;