rs112057482

Variant names:

• chrX-139561780-A-G
• rs112057482
• NM_000133.4:c.1095A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7 BP4 BA1

This summary comes from the ClinGen Evidence Repository: The NM_000133.3:c.1095A>G variant predicts a synonymous change, Ser365=. It is reported at a high frequency of 0.03271 (622/19015 alleles with 172 hemizygotes) in the African subpopulation in gnomAD v2.1.1, meeting the BA1 cut-off of >=0.0000556. The variant is not predicted to impact splicing, and the nucleotide position at which this variant occurs is not highly conserved, meeting the BP4 and BP7 criteria. To the best of our knowledge, the variant has not been reported in male patients with Hemophilia B. In summary, the 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, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10529870/MONDO:0010604/080

• Frequency:
  • Genomes: 𝑓 0.0095 (9 hom., 290 hem., cov: 22)
  • Exomes 𝑓: 0.0012 (10 hom. 391 hem.)
• Consequence: F9 NM_000133.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: -1.64
• Publications: 0 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 -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F9	NM_000133.4	MANE Select	c.1095A>G	p.Ser365Ser	synonymous	Exon 8 of 8	NP_000124.1
	F9	NM_001313913.2		c.981A>G	p.Ser327Ser	synonymous	Exon 7 of 7	NP_001300842.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F9	ENST00000218099.7	TSL:1 MANE Select	c.1095A>G	p.Ser365Ser	synonymous	Exon 8 of 8	ENSP00000218099.2
	F9	ENST00000394090.2	TSL:1	c.981A>G	p.Ser327Ser	synonymous	Exon 7 of 7	ENSP00000377650.2
	F9	ENST00000643157.1		n.1723+39A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00948 AC: 1062 AN: 112024 Hom.: 9 Cov.: 22

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00434

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000374

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.000226

Gnomad OTH AF: 0.00930

GnomAD2 exomes AF: 0.00290 AC: 532 AN: 183190 AF XY: 0.00199

Gnomad AFR exome AF: 0.0327

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000318

Gnomad OTH exome AF: 0.00221

GnomAD4 exome AF: 0.00123 AC: 1355 AN: 1098230 Hom.: 10 Cov.: 31 AF XY: 0.00108 AC XY: 391 AN XY: 363592

African (AFR) AF: 0.0334 AC: 883 AN: 26403

American (AMR) AF: 0.00301 AC: 106 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.000148 AC: 8 AN: 54143

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.00193 AC: 8 AN: 4137

European-Non Finnish (NFE) AF: 0.000210 AC: 177 AN: 842128

Other (OTH) AF: 0.00375 AC: 173 AN: 46096

GnomAD4 genome AF: 0.00949 AC: 1064 AN: 112075 Hom.: 9 Cov.: 22 AF XY: 0.00846 AC XY: 290 AN XY: 34261

African (AFR) AF: 0.0321 AC: 990 AN: 30810

American (AMR) AF: 0.00433 AC: 46 AN: 10618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3549

South Asian (SAS) AF: 0.000376 AC: 1 AN: 2662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6156

Middle Eastern (MID) AF: 0.00457 AC: 1 AN: 219

European-Non Finnish (NFE) AF: 0.000226 AC: 12 AN: 53202

Other (OTH) AF: 0.00918 AC: 14 AN: 1525

Alfa AF: 0.00781 Hom.: 27

Bravo AF: 0.0113

EpiCase AF: 0.000436

EpiControl AF: 0.000889

ClinVar

ClinVar submissions as Germline

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)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.96
DANN	Benign	0.44
PhyloP100		-1.6
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: rs112057482; hg19: chrX-138643939;