rs438601

Variant names:

• chrX-139537760-C-G
• rs438601
• NM_000133.4:c.277+374C>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.277+374C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 110,829 control chromosomes in the GnomAD database, including 1,267 homozygotes. There are 4,940 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 0.16 (1267 hom., 4940 hem., cov: 22)
• Consequence: F9 NM_000133.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4	c.277+374C>G		intron_variant	Intron 3 of 7	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.277+374C>G		intron_variant	Intron 3 of 6		NP_001300842.1
F9	XM_005262397.5	c.277+374C>G		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.277+374C>G		intron_variant	Intron 3 of 7	1	NM_000133.4	ENSP00000218099.2
F9	ENST00000394090.2	c.277+374C>G		intron_variant	Intron 3 of 6	1		ENSP00000377650.2
F9	ENST00000479617.2	n.241+605C>G		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.158 AC: 17522 AN: 110778 Hom.: 1270 Cov.: 22

Gnomad AFR AF: 0.0727

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.00369

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.251

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.143

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

GnomAD4 genome AF: 0.158 AC: 17514 AN: 110829 Hom.: 1267 Cov.: 22 AF XY: 0.149 AC XY: 4940 AN XY: 33055

African (AFR) AF: 0.0726 AC: 2219 AN: 30565

American (AMR) AF: 0.111 AC: 1157 AN: 10452

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 525 AN: 2633

East Asian (EAS) AF: 0.00398 AC: 14 AN: 3516

South Asian (SAS) AF: 0.130 AC: 337 AN: 2591

European-Finnish (FIN) AF: 0.175 AC: 1030 AN: 5869

Middle Eastern (MID) AF: 0.229 AC: 50 AN: 218

European-Non Finnish (NFE) AF: 0.223 AC: 11798 AN: 52798

Other (OTH) AF: 0.141 AC: 212 AN: 1507

Alfa AF: 0.190 Hom.: 1283

Bravo AF: 0.146

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.20
DANN	Benign	0.41
PhyloP100		-1.3
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: rs438601; hg19: chrX-138619919;