rs112057482

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4	c.1095A>G	p.Ser365Ser	synonymous_variant	Exon 8 of 8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.981A>G	p.Ser327Ser	synonymous_variant	Exon 7 of 7		NP_001300842.1
F9	XM_005262397.5	c.966A>G	p.Ser322Ser	synonymous_variant	Exon 7 of 7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.1095A>G	p.Ser365Ser	synonymous_variant	Exon 8 of 8	1	NM_000133.4	ENSP00000218099.2
F9	ENST00000394090.2	c.981A>G	p.Ser327Ser	synonymous_variant	Exon 7 of 7	1		ENSP00000377650.2
F9	ENST00000643157.1	n.1723+39A>G		intron_variant	Intron 6 of 6

Frequencies

GnomAD3 genomes AF: 0.00948 AC: 1062 AN: 112024 Hom.: 9 Cov.: 22 AF XY: 0.00845 AC XY: 289 AN XY: 34200

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

GnomAD3 exomes AF: 0.00290 AC: 532 AN: 183190 Hom.: 2 AF XY: 0.00199 AC XY: 135 AN XY: 67676

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 SAS exome AF: 0.0000524

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

Gnomad4 AFR exome AF: 0.0334

Gnomad4 AMR exome AF: 0.00301

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000148

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000210

Gnomad4 OTH exome AF: 0.00375

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

Gnomad4 AFR AF: 0.0321

Gnomad4 AMR AF: 0.00433

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000376

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000226

Gnomad4 OTH AF: 0.00918

Alfa AF: 0.00781 Hom.: 27

Bravo AF: 0.0113

EpiCase AF: 0.000436

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary factor IX deficiency disease Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 09, 2024

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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. -

not specified Benign:1

Jun 03, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.96
DANN	Benign	0.44

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: rs112057482; hg19: chrX-138643939;