rs112057482

Positions:

chrX-139561780-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4BA1BP7

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

Scores

Clinical Significance

Benign reviewed by expert panel B:5

Conservation

PhyloP100: -1.64

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

BP7

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
F9	NM_000133.4 linkuse as main transcript	c.1095A>G	p.Ser365=	synonymous_variant	8/8	ENST00000218099.7
F9	NM_001313913.2 linkuse as main transcript	c.981A>G	p.Ser327=	synonymous_variant	7/7
F9	XM_005262397.5 linkuse as main transcript	c.966A>G	p.Ser322=	synonymous_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F9	ENST00000218099.7 linkuse as main transcript	c.1095A>G	p.Ser365=	synonymous_variant	8/8	1	NM_000133.4	P1	P00740-1
F9	ENST00000394090.2 linkuse as main transcript	c.981A>G	p.Ser327=	synonymous_variant	7/7	1			P00740-2
F9	ENST00000643157.1 linkuse as main transcript	n.1723+39A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00948

AC:

1062

AN:

112024

Hom.:

Cov.:

AF XY:

0.00845

AC XY:

289

AN XY:

34200

show subpopulations

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.:

AF XY:

0.00199

AC XY:

135

AN XY:

67676

show subpopulations

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.:

Cov.:

AF XY:

0.00108

AC XY:

391

AN XY:

363592

show subpopulations

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.:

Cov.:

AF XY:

0.00846

AC XY:

290

AN XY:

34261

show subpopulations

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.:

Bravo

AF:

0.0113

EpiCase

AF:

0.000436

EpiControl

AF:

0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary factor IX deficiency disease

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, reviewed by expert panel	curation	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	Feb 09, 2024	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

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 03, 2019

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over