rs1800455

Positions:

chrX-139560836-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000133.4(F9):c.819T>C(p.Val273Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,198,637 control chromosomes in the GnomAD database, including 2 homozygotes. There are 599 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., 34 hem., cov: 23)

Exomes 𝑓: 0.0017 ( 2 hom. 565 hem. )

Consequence

F9
NM_000133.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.209

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant X-139560836-T-C is Benign according to our data. Variant chrX-139560836-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 10600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.209 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00113 (126/111966) while in subpopulation NFE AF= 0.00178 (95/53222). AF 95% confidence interval is 0.00149. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 34 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F9	NM_000133.4 link	c.819T>C	p.Val273Val	synonymous_variant	7/8	ENST00000218099.7	NP_000124.1	P00740-1
F9	NM_001313913.2 link	c.705T>C	p.Val235Val	synonymous_variant	6/7		NP_001300842.1	P00740-2
F9	XM_005262397.5 link	c.690T>C	p.Val230Val	synonymous_variant	6/7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
F9	ENST00000218099.7 link	c.819T>C	p.Val273Val	synonymous_variant	7/8	1	NM_000133.4	ENSP00000218099.2	P00740-1
F9	ENST00000394090.2 link	c.705T>C	p.Val235Val	synonymous_variant	6/7	1		ENSP00000377650.2	P00740-2
F9	ENST00000643157.1 link	n.1486T>C		non_coding_transcript_exon_variant	5/7

Frequencies

GnomAD3 genomes

AF:

0.00113

AC:

126

AN:

111914

Hom.:

Cov.:

AF XY:

0.000998

AC XY:

AN XY:

34082

show subpopulations

Gnomad AFR

AF:

0.0000974

Gnomad AMI

AF:

0.00292

Gnomad AMR

AF:

0.000758

Gnomad ASJ

AF:

0.00226

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000755

Gnomad FIN

AF:

0.00133

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.00178

Gnomad OTH

AF:

0.000662

GnomAD3 exomes

AF:

0.00137

AC:

251

AN:

183416

Hom.:

AF XY:

0.00149

AC XY:

101

AN XY:

67866

show subpopulations

Gnomad AFR exome

AF:

0.000304

Gnomad AMR exome

AF:

0.000510

Gnomad ASJ exome

AF:

0.00174

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00168

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00200

Gnomad OTH exome

AF:

0.000883

GnomAD4 exome

AF:

0.00166

AC:

1799

AN:

1086671

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

565

AN XY:

352505

show subpopulations

Gnomad4 AFR exome

AF:

0.000115

Gnomad4 AMR exome

AF:

0.000568

Gnomad4 ASJ exome

AF:

0.00238

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00154

Gnomad4 FIN exome

AF:

0.000864

Gnomad4 NFE exome

AF:

0.00183

Gnomad4 OTH exome

AF:

0.00184

GnomAD4 genome

AF:

0.00113

AC:

126

AN:

111966

Hom.:

Cov.:

AF XY:

0.000996

AC XY:

AN XY:

34144

show subpopulations

Gnomad4 AFR

AF:

0.0000971

Gnomad4 AMR

AF:

0.000757

Gnomad4 ASJ

AF:

0.00226

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000758

Gnomad4 FIN

AF:

0.00133

Gnomad4 NFE

AF:

0.00178

Gnomad4 OTH

AF:

0.000654

Alfa

AF:

0.00155

Hom.:

Bravo

AF:

0.00106

EpiCase

AF:

0.00251

EpiControl

AF:

0.00219

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

F9-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

- -

Hereditary factor IX deficiency disease

Benign:1

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

FACTOR IX, DNA POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Sep 01, 1989

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

1.6

DANN

Benign

0.50

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