X-139561835-C-T

Position:

chrX-139561835-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000133.4(F9):c.1150C>T(p.Arg384Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 111,885 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Consequence

F9
NM_000133.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 0.879

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 74 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-139561835-C-T is Pathogenic according to our data. Variant chrX-139561835-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
F9	NM_000133.4 linkuse as main transcript	c.1150C>T	p.Arg384Ter	stop_gained	8/8	ENST00000218099.7
F9	NM_001313913.2 linkuse as main transcript	c.1036C>T	p.Arg346Ter	stop_gained	7/7
F9	XM_005262397.5 linkuse as main transcript	c.1021C>T	p.Arg341Ter	stop_gained	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F9	ENST00000218099.7 linkuse as main transcript	c.1150C>T	p.Arg384Ter	stop_gained	8/8	1	NM_000133.4	P1	P00740-1
F9	ENST00000394090.2 linkuse as main transcript	c.1036C>T	p.Arg346Ter	stop_gained	7/7	1			P00740-2
F9	ENST00000643157.1 linkuse as main transcript	n.1723+94C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111885

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34065

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111885

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34065

show subpopulations

Gnomad4 AFR

AF:

0.0000326

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary factor IX deficiency disease

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1989	- -
Pathogenic, no assertion criteria provided	clinical testing	Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	Jun 01, 2019	- -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 14, 2019

The F9 c.1150C>T; p.Arg384Ter variant (rs137852261) is reported in the literature in multiple individuals affected with moderate to severe hemophilia B (Chen 1991, Giannelli 1994, Factor IX database and references therein). Functional assays indicate that patients with this variant exhibit clotting activity less than 1% of wildtype (Chen 1991, Giannelli 1994). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the F9 gene, which may not lead to nonsense-mediated decay but is expected to truncate the final 78 amino acids. Additionally, truncating variants downstream of p.Arg384Ter have been reported in individuals with hemophilia B and are considered disease-causing (Giannelli 1994). Based on available information, the p.Arg384Ter variant is considered to be pathogenic. References: Factor IX database: http://www.factorix.org Chen SH et al. CG dinucleotide transitions in the factor IX gene account for about half of the point mutations in hemophilia B patients: a Seattle series. Hum Genet. 1991 Jun;87(2):177-82. Giannelli F et al. Haemophilia B: database of point mutations and short additions and deletions, fifth edition, 1994. Nucleic Acids Res. 1994 Sep;22(17):3534-46. -

F9-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 06, 2023

The F9 c.1150C>T variant is predicted to result in premature protein termination (p.Arg384*). This variant, previously described as p.Arg338*, has been reported to be causative for Hemophilia B (Chen et al. 1991. PubMed ID: 2066105; Huang et al. 2020. PubMed ID: 32875744; Villarreal-Martínez et al. 2020. PubMed ID: 32224444). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in F9 are expected to be pathogenic. This variant is interpreted as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2023

This sequence change creates a premature translational stop signal (p.Arg384*) in the F9 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 78 amino acid(s) of the F9 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hemophilia B (PMID: 2066105, 2741941, 18624698, 22544209). This variant is also known as Arg338Stop. ClinVar contains an entry for this variant (Variation ID: 10615). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

FATHMM_MKL

Benign

0.49

MutationTaster

Benign

1.0

A;A

Vest4

0.66

GERP RS

3.8

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