rs3817939

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4	c.88+75A>G		intron_variant	Intron 1 of 7	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.88+75A>G		intron_variant	Intron 1 of 6		NP_001300842.1
F9	XM_005262397.5	c.88+75A>G		intron_variant	Intron 1 of 6		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.88+75A>G		intron_variant	Intron 1 of 7	1	NM_000133.4	ENSP00000218099.2
F9	ENST00000394090.2	c.88+75A>G		intron_variant	Intron 1 of 6	1		ENSP00000377650.2
F9	ENST00000479617.2	n.95+75A>G		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes AF: 0.0382 AC: 4276 AN: 111896 Hom.: 178 Cov.: 23 AF XY: 0.0414 AC XY: 1412 AN XY: 34082

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

Gnomad4 AFR exome AF: 0.00772

Gnomad4 AMR exome AF: 0.247

Gnomad4 ASJ exome AF: 0.0154

Gnomad4 EAS exome AF: 0.159

Gnomad4 SAS exome AF: 0.0498

Gnomad4 FIN exome AF: 0.0469

Gnomad4 NFE exome AF: 0.0179

Gnomad4 OTH exome AF: 0.0426

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

Gnomad4 AFR AF: 0.00873

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.178

Gnomad4 SAS AF: 0.0497

Gnomad4 FIN AF: 0.0438

Gnomad4 NFE AF: 0.0205

Gnomad4 OTH AF: 0.0475

Alfa AF: 0.0272 Hom.: 497

Bravo AF: 0.0509

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary factor IX deficiency disease Benign:1

Feb 09, 2024

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.5
DANN	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs3817939; hg19: chrX-138613086; COSMIC: COSV54382584;