rs137852247

Variant names:

• chrX-139560852-G-A
• rs137852247
• NM_000133.4:c.835G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-139560852-G-A
• chrX-139560852-G-C
• chrX-139560852-G-T

Variant summary

Our verdict is Pathogenic. The variant received 8 ACMG points: 8P and 0B. PS4 PP4_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000133.3:c.835G>A variant that results in the Ala279Thr missense change is absent from gnomAD v2.1.1 and v3, meeting PM2_Supporting. More than 59 male patients with mild hemophilia B are reported hemizygous for this variant in the literature, meeting PS4_Very strong and PP4_Moderate criteria (PMID:29296726, 29656491). It is noted as a founder variant but may also have arisen de novo as a recurrent variant and is found in multiple ethnicities. The variant has a REVEL score of 0.765 (>0.6) which meets the thresholds recommended for PP3. In summary, the 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, PP3, PP4_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA277507/MONDO:0010604/080

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 8.12
• Publications: 4 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 8 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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: 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.835G>A	p.Ala279Thr	missense	Exon 7 of 8	NP_000124.1	P00740-1
	F9	NM_001313913.2		c.721G>A	p.Ala241Thr	missense	Exon 6 of 7	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.835G>A	p.Ala279Thr	missense	Exon 7 of 8	ENSP00000218099.2	P00740-1
	F9	ENST00000394090.2	TSL:1	c.721G>A	p.Ala241Thr	missense	Exon 6 of 7	ENSP00000377650.2	P00740-2
	F9	ENST00000643157.1		n.1502G>A		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000190 AC: 2 AN: 1050721 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 321079

African (AFR) AF: 0.00 AC: 0 AN: 25551

American (AMR) AF: 0.00 AC: 0 AN: 35166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19089

East Asian (EAS) AF: 0.00 AC: 0 AN: 30027

South Asian (SAS) AF: 0.00 AC: 0 AN: 53058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4013

European-Non Finnish (NFE) AF: 0.00000250 AC: 2 AN: 798900

Other (OTH) AF: 0.00 AC: 0 AN: 44525

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Hereditary factor IX deficiency disease (5)
3	-	-	not provided (3)
1	-	-	Abnormality of coagulation (1)
1	-	-	Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect (1)
1	-	-	Hereditary factor VIII deficiency disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.9	M
PhyloP100		8.1
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.2	N
REVEL	Pathogenic	0.77
Sift	Benign	0.038	D
Sift4G	Uncertain	0.049	D
Polyphen		0.96	D
Vest4		0.70
MutPred		0.86		Gain of glycosylation at A279 (P = 0.0306)
MVP		1.0
MPC		1.4
ClinPred		0.93	D
GERP RS		5.8
Varity_R		0.63
gMVP		0.97
Mutation Taster		=12/88	disease causing (ClinVar)

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: rs137852247; hg19: chrX-138643011; COSMIC: COSV54378539;