chrX-139551220-G-A

Variant names:

• chrX-139551220-G-A
• rs137852242
• NM_000133.4:c.679G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 3P and 7B. PM1 PP2 BP4 BP6_Moderate BS2

The NM_000133.4(F9):​c.679G>A​(p.Val227Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,098,112 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000014 (0 hom. 5 hem.)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.416
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• hemophilia B

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• mild hemophilia B

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• moderately severe hemophilia B

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• severe hemophilia B

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• symptomatic form of hemophilia B in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• thrombophilia, X-linked, due to factor 9 defect

  Inheritance: XL Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000133.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 162 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 2.1809 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to hemophilia B, symptomatic form of hemophilia B in female carriers, thrombophilia, X-linked, due to factor 9 defect, mild hemophilia B, severe hemophilia B, moderately severe hemophilia B.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39294234).
• BP6: Variant X-139551220-G-A is Benign according to our data. Variant chrX-139551220-G-A is described in ClinVar as Benign. ClinVar VariationId is 1596936.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000133.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F9	NM_000133.4	MANE Select	c.679G>A	p.Val227Ile	missense	Exon 6 of 8	NP_000124.1
	F9	NM_001313913.2		c.565G>A	p.Val189Ile	missense	Exon 5 of 7	NP_001300842.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F9	ENST00000218099.7	TSL:1 MANE Select	c.679G>A	p.Val227Ile	missense	Exon 6 of 8	ENSP00000218099.2
	F9	ENST00000394090.2	TSL:1	c.565G>A	p.Val189Ile	missense	Exon 5 of 7	ENSP00000377650.2
	F9	ENST00000643157.1		n.1346G>A		non_coding_transcript_exon	Exon 4 of 7

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000654 AC: 12 AN: 183459 AF XY: 0.0000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000147

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 15 AN: 1098112 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 5 AN XY: 363468

African (AFR) AF: 0.00 AC: 0 AN: 26399

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.0000166 AC: 14 AN: 842007

Other (OTH) AF: 0.0000217 AC: 1 AN: 46094

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000824 AC: 10

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.19
DANN	Benign	0.25
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	-0.74	N
PhyloP100		-0.42
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.55	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.63		Loss of disorder (P = 0.1551)
MVP		0.64
MPC		0.56
ClinPred		0.015	T
GERP RS		0.51
Varity_R		0.15
gMVP		0.91
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137852242; hg19: chrX-138633379;