rs3817939

Variant names:

• chrX-139530927-A-G
• rs3817939
• NM_000133.4:c.88+75A>G

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.88+75A>G variant is reported at an MAF of 0.1727 (1595/9236 alleles) in the Latino population in gnomAD v3 with 580 hemizygotes and 103 homozygotes, meeting BA1 criteria of MAF > 0.0000556. The variant is listed as a polymorphism in the EAHAD database. SpliceAI predicts no impact on splicing, which meets the 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/CA336128584/MONDO:0010604/080

• Frequency:
  • Genomes: 𝑓 0.038 (180 hom., 1411 hem., cov: 23)
  • Exomes 𝑓: 0.037 (1283 hom. 8856 hem.)
• Consequence: F9 NM_000133.4 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: 0.997
• 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

Specifications for F9 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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.88+75A>G		intron	N/A	NP_000124.1	P00740-1
	F9	NM_001313913.2		c.88+75A>G		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.88+75A>G		intron	N/A	ENSP00000218099.2	P00740-1
	F9	ENST00000394090.2	TSL:1	c.88+75A>G		intron	N/A	ENSP00000377650.2	P00740-2
	F9	ENST00000479617.2	TSL:5	n.95+75A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0382 AC: 4276 AN: 111896 Hom.: 178 Cov.: 23

Gnomad AFR AF: 0.00875

Gnomad AMI AF: 0.00145

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.0518

Gnomad FIN AF: 0.0438

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0205

Gnomad OTH AF: 0.0481

GnomAD4 exome AF: 0.0369 AC: 29074 AN: 787394 Hom.: 1283 AF XY: 0.0415 AC XY: 8856 AN XY: 213578

African (AFR) AF: 0.00772 AC: 158 AN: 20472

American (AMR) AF: 0.247 AC: 8386 AN: 33929

Ashkenazi Jewish (ASJ) AF: 0.0154 AC: 267 AN: 17323

East Asian (EAS) AF: 0.159 AC: 4522 AN: 28486

South Asian (SAS) AF: 0.0498 AC: 2349 AN: 47171

European-Finnish (FIN) AF: 0.0469 AC: 1697 AN: 36211

Middle Eastern (MID) AF: 0.0254 AC: 87 AN: 3424

European-Non Finnish (NFE) AF: 0.0179 AC: 10079 AN: 564523

Other (OTH) AF: 0.0426 AC: 1529 AN: 35855

GnomAD4 genome AF: 0.0382 AC: 4274 AN: 111950 Hom.: 180 Cov.: 23 AF XY: 0.0413 AC XY: 1411 AN XY: 34146

African (AFR) AF: 0.00873 AC: 270 AN: 30938

American (AMR) AF: 0.171 AC: 1784 AN: 10462

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 26 AN: 2656

East Asian (EAS) AF: 0.178 AC: 627 AN: 3531

South Asian (SAS) AF: 0.0497 AC: 133 AN: 2674

European-Finnish (FIN) AF: 0.0438 AC: 266 AN: 6070

Middle Eastern (MID) AF: 0.0278 AC: 6 AN: 216

European-Non Finnish (NFE) AF: 0.0205 AC: 1088 AN: 53179

Other (OTH) AF: 0.0475 AC: 73 AN: 1536

Alfa AF: 0.0268 Hom.: 750

Bravo AF: 0.0509

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary factor IX deficiency disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.5
DANN	Benign	0.65
PhyloP100		1.0
PromoterAI		0.067	Neutral
Mutation Taster		=100/0	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: rs3817939; hg19: chrX-138613086; COSMIC: COSV54382584;