rs137852249

Variant names:

• chrX-139561566-G-A
• rs137852249
• NM_000133.4:c.881G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-139561566-G-A
• chrX-139561566-G-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PS4 PS3_Supporting PP4_Moderate PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.881G>A, p.Arg294Gln variant affects one of the functional domains (aa 227-459; Peptidase S1 domain) in the F9 protein meeting PM1. The variant is absent from male population databases (gnomAD v4.1) meeting PM2_Supporting. At least 30 patients with mild, moderate or severe hemophilia B have been reported in the literature reviewed meeting PS4_Very Strong and PP4_Moderate (PMID:29296726, 15921378, 8091381). In-vitro functional studies show that the variant causes ER retention of the F9 protein, leading to reduced antigen levels meeting PS3_Supporting. REVEL score for this variant does not fall within the thresholds for pathogenic or benign predictions, and no splicing impact is noted by SpliceAI. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Very Strong, PM1, PP4_Moderate, PS3_Supporting, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA255368/MONDO:0010604/080

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: F9 ENST00000218099.7 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 2.44
• Publications: 11 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: Pathogenic. The variant received 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000218099.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F9	NM_000133.4	MANE Select	c.881G>A	p.Arg294Gln	missense	Exon 8 of 8	NP_000124.1
	F9	NM_001313913.2		c.767G>A	p.Arg256Gln	missense	Exon 7 of 7	NP_001300842.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F9	ENST00000218099.7	TSL:1 MANE Select	c.881G>A	p.Arg294Gln	missense	Exon 8 of 8	ENSP00000218099.2
	F9	ENST00000394090.2	TSL:1	c.767G>A	p.Arg256Gln	missense	Exon 7 of 7	ENSP00000377650.2
	F9	ENST00000643157.1		n.1548G>A		non_coding_transcript_exon	Exon 6 of 7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1094036 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 359734

African (AFR) AF: 0.00 AC: 0 AN: 26335

American (AMR) AF: 0.00 AC: 0 AN: 34984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19246

East Asian (EAS) AF: 0.00 AC: 0 AN: 30129

South Asian (SAS) AF: 0.00 AC: 0 AN: 53429

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40443

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4120

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 839436

Other (OTH) AF: 0.00 AC: 0 AN: 45914

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000219

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	-	-	Hereditary factor IX deficiency disease (8)
1	-	-	Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect (1)
1	-	-	Hereditary factor VIII deficiency disease (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.7	L
PhyloP100		2.4
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.58
Sift	Benign	0.080	T
Sift4G	Benign	0.18	T
Polyphen		0.99	D
Vest4		0.33
MutPred		0.90		Loss of methylation at K293 (P = 0.0676)
MVP		0.99
MPC		1.8
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.87
gMVP		0.96
Mutation Taster		=21/79	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137852249; hg19: chrX-138643725; COSMIC: COSV54379618;