X-139541114-G-A

Position:

chrX-139541114-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3PP1PP4_ModeratePS4PM1

This summary comes from the ClinGen Evidence Repository: The c.316G>A (p.Gly106Ser) variant affects one of the functional domains (aa 93-129; EGF-like 1 domain) in the F9 protein, meeting the PM1 criteria. This missense variant has a REVEL score of 0.905(>0.6), meeting the PP3 criteria. It is reported at an MAF of 0.00002441 (5/204867 alleles) in the overall population in gnomAD v2.1.1, with 3 hemizygotes; however BS1 criteria of MAF >=0.0000278 is not met. Over 60 patients with mild and moderate hemophilia B are reported in the literature meeting PS4_Very strong and PP4_Moderate criteria (PMID:22103590, 29296726). In summary, the clinical significance of this variant is pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Very strong, PM1, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA255329/MONDO:0010604/080

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.0000074 ( 0 hom. 3 hem. )

Consequence

F9
NM_000133.4 missense

Scores

9

6

2

Clinical Significance

Pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 8.98

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 10 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F9	NM_000133.4 linkuse as main transcript	c.316G>A	p.Gly106Ser	missense_variant	4/8	ENST00000218099.7	NP_000124.1
F9	XM_005262397.5 linkuse as main transcript	c.316G>A	p.Gly106Ser	missense_variant	4/7		XP_005262454.1
F9	NM_001313913.2 linkuse as main transcript	c.277+3728G>A		intron_variant			NP_001300842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7 linkuse as main transcript	c.316G>A	p.Gly106Ser	missense_variant	4/8	1	NM_000133.4	ENSP00000218099	P1	P00740-1
F9	ENST00000394090.2 linkuse as main transcript	c.277+3728G>A		intron_variant		1		ENSP00000377650		P00740-2
F9	ENST00000479617.2 linkuse as main transcript	n.269G>A		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes

AF:

0.0000359

AC:

4

AN:

111504

Hom.:

0

Cov.:

23

AF XY:

0.0000593

AC XY:

2

AN XY:

33710

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000956

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000166

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

2

AN:

183001

Hom.:

0

AF XY:

0.0000296

AC XY:

2

AN XY:

67603

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000736

AC:

8

AN:

1087481

Hom.:

0

Cov.:

28

AF XY:

0.00000845

AC XY:

3

AN XY:

355229

show subpopulations

Gnomad4 AFR exome

AF:

0.0000384

Gnomad4 AMR exome

AF:

0.0000287

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000599

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000359

AC:

4

AN:

111504

Hom.:

0

Cov.:

23

AF XY:

0.0000593

AC XY:

2

AN XY:

33710

show subpopulations

Gnomad4 AFR

AF:

0.0000326

Gnomad4 AMR

AF:

0.0000956

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000166

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

ESP6500AA

AF:

0.00

AC:

0

ESP6500EA

AF:

0.000149

AC:

1

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary factor IX deficiency disease

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 25, 1989	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	Feb 09, 2024	The c.316G>A (p.Gly106Ser) variant affects one of the functional domains (aa 93-129; EGF-like 1 domain) in the F9 protein, meeting the PM1 criteria. This missense variant has a REVEL score of 0.905(>0.6), meeting the PP3 criteria. It is reported at an MAF of 0.00002441 (5/204867 alleles) in the overall population in gnomAD v2.1.1, with 3 hemizygotes; however BS1 criteria of MAF >=0.0000278 is not met. Over 60 patients with mild and moderate hemophilia B are reported in the literature meeting PS4_Very strong and PP4_Moderate criteria (PMID: 22103590, 29296726). In summary, the clinical significance of this variant is pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Very strong, PM1, PP4_Moderate, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 27, 2023	The F9 c.316G>A missense variant has been classified as Pathogenic (PS4_Strong, PP3, PS3_Moderate, PP1_Moderate, PP4). The c.316G>A variant is a single nucleotide change in exon 4/8 of the F9 gene, which is predicted to change the amino acid glycine at position 106 in the protein to serine. This variant is in gnomAD at very low frequency (0.003%, allele count 4/111504, 2 hemizygous) and has been reported in numerous affected individuals with mild haemophilia B (PMID:22639855, 35842956, and 2472424) (PS4_strong). Note that this variant has been previously reported in the literature as p.Gly60Ser. Computational data predicts a deleterious effect (PP3). This variant is located in the functional cbEGF domain and has been predicted to affect protein folding (PMID: 9525872) (PS3_moderate). The variant has been shown to segregate with disease in 2 patients and a proband from 2 families (PMID: 2472424, 3651597) and has been reported to have been found in at least 5 generations (PP1_Moderate). The patient's family history and FIX bioassay levels are consistent with the specific gene aetiology (PP4). This variant is a missense change at an amino acid residue where different missense changes have been seen before: p.Gly106Arg (CM940467), p.Gly106Asp (CM940465), p.Gly106Cys (CM960576). This variant has been reported in dbSNP (rs137852233), HGMD as disease causing (CM940466) and in ClinVar as pathogenic (ClinVar variant ID: 10579). -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 17, 2021	The F9 c.316G>A; p.Gly106Ser variant (rs1378522233), also known as Gly60Ser or FIX Durham, is reported in numerous patients diagnosed with mild hemophilia B (Chavali 2009, Chen 1989, Denton 1988, Poort 1989, Factor IX Variant Database and references therein). This variant is reported as pathogenic in ClinVar (Variation ID: 10579) and is found in the general population at a low overall allele frequency of 0.003% (5/204867 alleles, including 3 hemizygotes) in the Genome Aggregation Database. The glycine at codon 106 is highly conserved and located in the calcium-binding EGF-like domain. Structural analyses demonstrate that the variant increases the likelihood of defective folding in the EGF-like domain of the protein (Whiteman 1998). Additionally, other amino acid substitutions at this codon (Arg, Cys, and Asp) have been reported in individuals with hemophilia B and are considered disease-causing (Factor IX Variant Database and references therein). Based on available information, the p.Gly106Ser variant is considered to be pathogenic. References: Factor IX Variant Database: http://f9-db.eahad.org/ Chavali S et al. Hemophilia B is a quasi-quantitative condition with certain mutations showing phenotypic plasticity. Genomics. 2009 Dec;94(6):433-7. Chen SH et al. Three point mutations in the factor IX genes of five hemophilia B patients. Identification strategy using localization by altered epitopes in their hemophilic proteins. J Clin Invest. 1989 Jul;84(1):113-8. Denton PH et al. Hemophilia B Durham: a mutation in the first EGF-like domain of factor IX that is characterized by polymerase chain reaction. Blood. 1988 Oct;72(4):1407-11. Poort SR et al. A Dutch pedigree with mild hemophilia B with a missense mutation in the first EGF domain (factor IXOud en Nieuw Gastel). Nucleic Acids Res. 1989 Jul 25;17(14):5869. Whiteman P et al. A Gly --> Ser change causes defective folding in vitro of calcium-binding epidermal growth factor-like domains from factor IX and fibrillin-1. J Biol Chem. 1998 Apr 3;273(14):7807-13. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 29, 2022	PP3, PP5, PM1_supporting, PM5, PS3, PS4_moderate -

F9-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2024

The F9 c.316G>A variant is predicted to result in the amino acid substitution p.Gly106Ser. This variant, also referred to as Hemophilia B Durham, has been reported previously in many patients to be causative for Hemophilia B (Denton et al. 1988. PubMed ID: 3262389; Tengguo et al. 2014. PubMed ID: 24375831; Factor IX Gene (F9) Variant Database: http://www.factorix.org/). Several other missense changes at this same position (p.Gly106Cys, p.Gly106Arg, and p.Gly106Asp) have also been reported to be causative for Hemophilia B (Factor IX Gene (F9) Variant Database: http://www.factorix.org/). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD. The c.316G>A (p.Gly106Ser) 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 106 of the F9 protein (p.Gly106Ser). This variant is present in population databases (rs137852233, gnomAD 0.01%). This missense change has been observed in individuals with mild hemophilia B (PMID: 2472424, 19699296, 22639855). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly60Ser, 10430G>A, and FIX Durham. ClinVar contains an entry for this variant (Variation ID: 10579). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt F9 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on F9 function (PMID: 9525872). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Thrombophilia, X-linked, due to factor 9 defect

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect;C5393318:Warfarin sensitivity, X-linked

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.55

D

BayesDel_noAF

Pathogenic

0.74

CADD

Uncertain

26

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Uncertain

0.96

D

M_CAP

Pathogenic

0.94

D

MetaRNN

Pathogenic

0.97

D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Uncertain

2.9

M

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.49

T

PROVEAN

Pathogenic

-4.7

D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0040

D

Sift4G

Uncertain

0.0070

D

Polyphen

1.0

D

Vest4

0.81

MVP

1.0

MPC

2.9

ClinPred

0.97

D

GERP RS

5.8

Varity_R

0.92

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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.

Other links and lift over

dbSNP: rs137852233; hg19: chrX-138623273; COSMIC: COSV54382023; COSMIC: COSV54382023;