X-139541073-A-G

Variant names:

• chrX-139541073-A-G
• rs398122990
• NM_000133.4:c.278-3A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_000133.4(F9):​c.278-3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000936 in 1,068,145 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
• Consequence: F9 NM_000133.4 splice_region, intron
• Scores: Splicing: ADA: 0.9254
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 1.53
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-139541073-A-G is Pathogenic according to our data. Variant chrX-139541073-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 92225.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4	c.278-3A>G		splice_region_variant, intron_variant	Intron 3 of 7	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.277+3687A>G		intron_variant	Intron 3 of 6		NP_001300842.1
F9	XM_005262397.5	c.278-3A>G		splice_region_variant, 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.278-3A>G		splice_region_variant, intron_variant	Intron 3 of 7	1	NM_000133.4	ENSP00000218099.2
F9	ENST00000394090.2	c.277+3687A>G		intron_variant	Intron 3 of 6	1		ENSP00000377650.2
F9	ENST00000479617.2	n.242-14A>G		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.36e-7 AC: 1 AN: 1068145 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 339217

African (AFR) AF: 0.00 AC: 0 AN: 25654

American (AMR) AF: 0.00 AC: 0 AN: 34637

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18631

East Asian (EAS) AF: 0.00 AC: 0 AN: 29094

South Asian (SAS) AF: 0.00 AC: 0 AN: 53480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39181

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3993

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 818966

Other (OTH) AF: 0.00 AC: 0 AN: 44509

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary factor IX deficiency disease Pathogenic:1 Other:1

Nov 06, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

SNPedia

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect Pathogenic:1

Mar 29, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change falls in intron 3 of the F9 gene. It does not directly change the encoded amino acid sequence of the F9 protein, but it affects a nucleotide within the consensus splice site of the intron. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hemophilia B (PMID: 28834196, 18624698, 8434583). This variant is also known as IVS3-3A>G and 10389A>G. ClinVar contains an entry for this variant (Variation ID: 92225). Experimental studies have shown that this variant disrupts mRNA splicing and is expected to lead to the loss of protein expression (PMID: 19815722, 28834196).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Benign	0.85
PhyloP100		1.5
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Benign	0.47
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.44		Position offset: 1
DS_AL_spliceai		0.35		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs398122990; hg19: chrX-138623232;