NM_000133.4:c.580A>G

Variant names:

• chrX-139551121-A-G
• rs6048
• NM_000133.4:c.580A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: The c.580A>G (p.Thr194Ala) variant is reported at an MAF of 0.3026 (27985/92495 alleles) in the non-Finnish European population in gnomAD v2.1.1 with 2609 homozygotes and 10667 hemizygotes, meeting BA1 criteria of MAF > 0.0000556. Note that gnomAD v3.1.1 reports a frequency of 0.3041 in the NFE population, with 1859 homozygotes and 4024 hemizygotes. This missense variant has a REVEL score of 0.255 (<0.3) and SpliceAI predicts no impact on splicing, with a score of 0.0, meeting BP4 criteria. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA121125/MONDO:0010604/080

• Frequency:
  • Genomes: 𝑓 0.22 (2307 hom., 7148 hem., cov: 23)
  • Exomes 𝑓: 0.27 (29445 hom. 98085 hem.)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Benign reviewed by expert panel B:12
• Conservation: PhyloP100: 0.555
• Publications: 36 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 -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.580A>G	p.Thr194Ala	missense	Exon 6 of 8	NP_000124.1	P00740-1
	F9	NM_001313913.2		c.466A>G	p.Thr156Ala	missense	Exon 5 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.580A>G	p.Thr194Ala	missense	Exon 6 of 8	ENSP00000218099.2	P00740-1
	F9	ENST00000394090.2	TSL:1	c.466A>G	p.Thr156Ala	missense	Exon 5 of 7	ENSP00000377650.2	P00740-2
	F9	ENST00000643157.1		n.1247A>G		non_coding_transcript_exon	Exon 4 of 7

Frequencies

GnomAD3 genomes AF: 0.223 AC: 24831 AN: 111270 Hom.: 2310 Cov.: 23

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.00392

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.217 AC: 39784 AN: 183245 AF XY: 0.225

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.00253

Gnomad FIN exome AF: 0.266

Gnomad NFE exome AF: 0.303

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.273 AC: 299272 AN: 1097623 Hom.: 29445 Cov.: 31 AF XY: 0.270 AC XY: 98085 AN XY: 363129

African (AFR) AF: 0.126 AC: 3318 AN: 26399

American (AMR) AF: 0.108 AC: 3789 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 4643 AN: 19384

East Asian (EAS) AF: 0.00136 AC: 41 AN: 30206

South Asian (SAS) AF: 0.177 AC: 9591 AN: 54133

European-Finnish (FIN) AF: 0.271 AC: 10969 AN: 40525

Middle Eastern (MID) AF: 0.275 AC: 1137 AN: 4132

European-Non Finnish (NFE) AF: 0.302 AC: 254229 AN: 841577

Other (OTH) AF: 0.251 AC: 11555 AN: 46065

GnomAD4 genome AF: 0.223 AC: 24829 AN: 111325 Hom.: 2307 Cov.: 23 AF XY: 0.213 AC XY: 7148 AN XY: 33559

African (AFR) AF: 0.132 AC: 4053 AN: 30725

American (AMR) AF: 0.148 AC: 1560 AN: 10507

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 611 AN: 2647

East Asian (EAS) AF: 0.00422 AC: 15 AN: 3556

South Asian (SAS) AF: 0.164 AC: 433 AN: 2643

European-Finnish (FIN) AF: 0.262 AC: 1552 AN: 5918

Middle Eastern (MID) AF: 0.266 AC: 57 AN: 214

European-Non Finnish (NFE) AF: 0.304 AC: 16091 AN: 52916

Other (OTH) AF: 0.181 AC: 275 AN: 1519

Alfa AF: 0.268 Hom.: 30725

Bravo AF: 0.207

TwinsUK AF: 0.299 AC: 1107

ALSPAC AF: 0.300 AC: 867

ESP6500AA AF: 0.124 AC: 474

ESP6500EA AF: 0.298 AC: 2007

ExAC AF: 0.224 AC: 27172

EpiCase AF: 0.293

EpiControl AF: 0.302

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary factor IX deficiency disease (4)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect (1)
-	-	1	Thrombophilia, X-linked, due to factor 9 defect (1)
-	-	-	Deep venous thrombosis, protection against (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.53
DANN	Benign	0.39
DEOGEN2	Benign	0.38	T
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.56
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.26
Sift	Benign	0.65	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.064
MPC		0.62
ClinPred		0.0019	T
GERP RS		1.2
Varity_R		0.059
gMVP		0.93
Mutation Taster		=89/11	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: rs6048; hg19: chrX-138633280; COSMIC: COSV54379523; COSMIC: COSV54379523;