chrX-139530815-C-T

Variant names:

• chrX-139530815-C-T
• rs774612303
• NM_000133.4:c.51C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_000133.4:c.51C>T (p.Ile17=) synonymous variant is reported at a high MAF of 0.004462 (125/28017 alleles with 31 hemizygotes) in the Latino population of gnomAD v2.1.1, meeting the BA1 cut-off of >/= 0.0000556. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency VCEP for F9: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10529714/MONDO:0010604/080

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., 5 hem., cov: 24)
  • Exomes 𝑓: 0.00013 (0 hom. 34 hem.)
• Consequence: F9 NM_000133.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: 0.121
• Publications: 3 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 -8 ACMG points.

• 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.51C>T	p.Ile17Ile	synonymous	Exon 1 of 8	NP_000124.1	P00740-1
	F9	NM_001313913.2		c.51C>T	p.Ile17Ile	synonymous	Exon 1 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.51C>T	p.Ile17Ile	synonymous	Exon 1 of 8	ENSP00000218099.2	P00740-1
	F9	ENST00000394090.2	TSL:1	c.51C>T	p.Ile17Ile	synonymous	Exon 1 of 7	ENSP00000377650.2	P00740-2
	F9	ENST00000479617.2	TSL:5	n.58C>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.000107 AC: 12 AN: 112482 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00114

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000677 AC: 124 AN: 183099 AF XY: 0.000443

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00453

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: 0.000130 AC: 143 AN: 1096890 Hom.: 0 Cov.: 29 AF XY: 0.0000938 AC XY: 34 AN XY: 362368

African (AFR) AF: 0.00 AC: 0 AN: 26370

American (AMR) AF: 0.00389 AC: 137 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19369

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.00 AC: 0 AN: 54118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40517

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 840941

Other (OTH) AF: 0.0000651 AC: 3 AN: 46052

GnomAD4 genome AF: 0.000107 AC: 12 AN: 112482 Hom.: 0 Cov.: 24 AF XY: 0.000144 AC XY: 5 AN XY: 34650

African (AFR) AF: 0.00 AC: 0 AN: 30994

American (AMR) AF: 0.00114 AC: 12 AN: 10572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3586

South Asian (SAS) AF: 0.00 AC: 0 AN: 2731

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6173

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53335

Other (OTH) AF: 0.00 AC: 0 AN: 1508

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000355

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary factor IX deficiency disease (2)
-	-	1	Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.2
DANN	Benign	0.77
PhyloP100		0.12
PromoterAI		-0.0072	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs774612303; hg19: chrX-138612974;