X-139530795-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000133.4(F9):c.31T>A(p.Ser11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 112,452 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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 Pathogenic (no stars).

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.482

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-139530795-T-A is Pathogenic according to our data. Variant chrX-139530795-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 10656.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.102716416).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F9	NM_000133.4	c.31T>A	p.Ser11Thr	missense_variant	1/8	ENST00000218099.7
F9	NM_001313913.2	c.31T>A	p.Ser11Thr	missense_variant	1/7
F9	XM_005262397.5	c.31T>A	p.Ser11Thr	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F9	ENST00000218099.7	c.31T>A	p.Ser11Thr	missense_variant	1/8	1	NM_000133.4	P1
F9	ENST00000394090.2	c.31T>A	p.Ser11Thr	missense_variant	1/7	1
F9	ENST00000479617.2	n.38T>A		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.00000889 AC: 1 AN: 112452 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34616

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000889 AC: 1 AN: 112452 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34616

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary factor IX deficiency disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	3.8
Dann	Benign	0.56
DEOGEN2	Benign	0.27	T;.
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.48	T;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.12	N;N
REVEL	Benign	0.21
Sift	Benign	0.50	T;T
Sift4G	Benign	0.69	T;T
Polyphen		0.0090	B;.
Vest4		0.24
MutPred		0.27		Loss of disorder (P = 0.1078);Loss of disorder (P = 0.1078);
MVP		0.74
MPC		0.068
ClinPred		0.089	T
GERP RS		-4.7
Varity_R		0.083
gMVP		0.62

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: rs387906480; hg19: chrX-138612954;