NM_000133.4:c.316G>A

Variant names:

• chrX-139541114-G-A
• rs137852233
• NM_000133.4:c.316G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PS4 PP4_Moderate PP3 PP1

This summary comes from the ClinGen Evidence Repository: The c.316G>A (p.Gly106Ser) variant affects one of the functional domains (aa 93-129; EGF-like 1 domain) in the F9 protein, meeting the PM1 criteria. This missense variant has a REVEL score of 0.905(>0.6), meeting the PP3 criteria. It is reported at an MAF of 0.00002441 (5/204867 alleles) in the overall population in gnomAD v2.1.1, with 3 hemizygotes; however BS1 criteria of MAF >=0.0000278 is not met. Over 60 patients with mild and moderate hemophilia B are reported in the literature meeting PS4_Very strong and PP4_Moderate criteria (PMID:22103590, 29296726). In summary, the clinical significance of this variant is pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Very strong, PM1, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA255329/MONDO:0010604/080

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.0000074 (0 hom. 3 hem.)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 8.98
• Publications: 12 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 10 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.316G>A	p.Gly106Ser	missense	Exon 4 of 8	NP_000124.1	P00740-1
	F9	NM_001313913.2		c.277+3728G>A		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.316G>A	p.Gly106Ser	missense	Exon 4 of 8	ENSP00000218099.2	P00740-1
	F9	ENST00000394090.2	TSL:1	c.277+3728G>A		intron	N/A	ENSP00000377650.2	P00740-2
	F9	ENST00000479617.2	TSL:5	n.269G>A		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.0000359 AC: 4 AN: 111504 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000956

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183001 AF XY: 0.0000296

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000736 AC: 8 AN: 1087481 Hom.: 0 Cov.: 28 AF XY: 0.00000845 AC XY: 3 AN XY: 355229

African (AFR) AF: 0.0000384 AC: 1 AN: 26073

American (AMR) AF: 0.0000287 AC: 1 AN: 34903

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19003

East Asian (EAS) AF: 0.00 AC: 0 AN: 29652

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53883

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39807

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4067

European-Non Finnish (NFE) AF: 0.00000599 AC: 5 AN: 834707

Other (OTH) AF: 0.00 AC: 0 AN: 45386

GnomAD4 genome AF: 0.0000359 AC: 4 AN: 111504 Hom.: 0 Cov.: 23 AF XY: 0.0000593 AC XY: 2 AN XY: 33710

African (AFR) AF: 0.0000326 AC: 1 AN: 30672

American (AMR) AF: 0.0000956 AC: 1 AN: 10463

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3538

South Asian (SAS) AF: 0.00 AC: 0 AN: 2657

European-Finnish (FIN) AF: 0.000166 AC: 1 AN: 6040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53083

Other (OTH) AF: 0.00 AC: 0 AN: 1492

Alfa AF: 0.00 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Hereditary factor IX deficiency disease (5)
2	-	-	not provided (2)
1	-	-	F9-related disorder (1)
1	-	-	Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect (1)
1	-	-	Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect;C5393318:Warfarin sensitivity, X-linked (1)
1	-	-	Thrombophilia, X-linked, due to factor 9 defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.74
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.81
MVP		1.0
MPC		2.9
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.92
gMVP		1.0
Mutation Taster		=31/69	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs137852233; hg19: chrX-138623273; COSMIC: COSV54382023; COSMIC: COSV54382023;