rs200608775

chrX-139560786-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000133.4(F9):c.769G>A(p.Val257Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,209,089 control chromosomes in the GnomAD database, including 1 homozygotes. There are 85 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.00020 (1 hom. 83 hem.)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.992

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 -11 ACMG points.

• PM1: In a domain Peptidase S1 (size 232) in uniprot entity FA9_HUMAN there are 152 pathogenic changes around while only 8 benign (95%) in NM_000133.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.025891602).
• BP6: Variant X-139560786-G-A is Benign according to our data. Variant chrX-139560786-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225354.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0002 (219/1097324) while in subpopulation EAS AF= 0.00659 (199/30192). AF 95% confidence interval is 0.00584. There are 1 homozygotes in gnomad4_exome. There are 83 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F9	NM_000133.4	c.769G>A	p.Val257Ile	missense_variant	7/8	ENST00000218099.7
F9	NM_001313913.2	c.655G>A	p.Val219Ile	missense_variant	6/7
F9	XM_005262397.5	c.640G>A	p.Val214Ile	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F9	ENST00000218099.7	c.769G>A	p.Val257Ile	missense_variant	7/8	1	NM_000133.4	P1
F9	ENST00000394090.2	c.655G>A	p.Val219Ile	missense_variant	6/7	1
F9	ENST00000643157.1	n.1436G>A		non_coding_transcript_exon_variant	5/7

Frequencies

GnomAD3 genomes AF: 0.000107 AC: 12 AN: 111714 Hom.: 0 Cov.: 23 AF XY: 0.0000590 AC XY: 2 AN XY: 33896

Gnomad AFR AF: 0.000163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000951

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00112

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000167

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000664

GnomAD3 exomes AF: 0.000125 AC: 23 AN: 183446 Hom.: 0 AF XY: 0.000103 AC XY: 7 AN XY: 67892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00152

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000200 AC: 219 AN: 1097324 Hom.: 1 Cov.: 29 AF XY: 0.000229 AC XY: 83 AN XY: 362734

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00659

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000741

Gnomad4 NFE exome AF: 0.00000951

Gnomad4 OTH exome AF: 0.000109

GnomAD4 genome AF: 0.000107 AC: 12 AN: 111765 Hom.: 0 Cov.: 23 AF XY: 0.0000589 AC XY: 2 AN XY: 33957

Gnomad4 AFR AF: 0.000162

Gnomad4 AMR AF: 0.0000950

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00112

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000167

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000656

Alfa AF: 0.000183 Hom.: 4

Bravo AF: 0.000106

ExAC AF: 0.000165 AC: 20

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary factor IX deficiency disease Uncertain:1 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. -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 07, 2020	- -

F9-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2024

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

Invitae

Jan 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	0.0030
Dann	Benign	0.61
DEOGEN2	Benign	0.39	T;.
FATHMM_MKL	Benign	0.0087	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.026	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-1.1	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.81	N;N
REVEL	Uncertain	0.48
Sift	Benign	0.49	T;T
Sift4G	Benign	0.41	T;T
Polyphen		0.0	B;.
Vest4		0.40
MVP		0.98
MPC		0.52
ClinPred		0.020	T
GERP RS		-5.8
Varity_R		0.051
gMVP		0.90

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: rs200608775; hg19: chrX-138642945; COSMIC: COSV54379507;