rs137852236

Positions:

• chrX-139548467-A-G
• chrX-139548467-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PM1 PM5 BP4_Moderate BS2

The NM_000133.4(F9):​c.496A>G​(p.Asn166Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,096,819 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N166Y) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000017 (0 hom. 7 hem.)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74

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 Likely_benign. Variant got -2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000133.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-139548467-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 10582.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16443467).
• BS2: High Hemizygotes in GnomAdExome4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F9	NM_000133.4	c.496A>G	p.Asn166Asp	missense_variant	5/8	ENST00000218099.7
F9	NM_001313913.2	c.382A>G	p.Asn128Asp	missense_variant	4/7
F9	XM_005262397.5	c.392-2595A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F9	ENST00000218099.7	c.496A>G	p.Asn166Asp	missense_variant	5/8	1	NM_000133.4	P1
F9	ENST00000394090.2	c.382A>G	p.Asn128Asp	missense_variant	4/7	1
F9	ENST00000643157.1	n.1163A>G		non_coding_transcript_exon_variant	3/7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000173 AC: 19 AN: 1096819 Hom.: 0 Cov.: 29 AF XY: 0.0000193 AC XY: 7 AN XY: 362399

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000226

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.6
DANN	Benign	0.28
DEOGEN2	Benign	0.40	T;.
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.74	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-1.5	N;.
MutationTaster	Benign	0.82	D;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	2.9	N;N
REVEL	Benign	0.21
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.052
MutPred		0.78		Gain of ubiquitination at K168 (P = 0.0913);.;
MVP		0.76
MPC		0.72
ClinPred		0.027	T
GERP RS		2.0
Varity_R		0.32
gMVP		0.95

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: rs137852236; hg19: chrX-138630626;