chrX-139530795-T-C

Variant names:

• chrX-139530795-T-C
• rs387906480
• NM_000133.4:c.31T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM2 PM5 PP2 BP4_Moderate

The NM_000133.4(F9):​c.31T>C​(p.Ser11Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,097,187 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 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. S11T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.482
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-139530795-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 10656.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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=0.11003867).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4	c.31T>C	p.Ser11Pro	missense_variant	Exon 1 of 8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.31T>C	p.Ser11Pro	missense_variant	Exon 1 of 7		NP_001300842.1
F9	XM_005262397.5	c.31T>C	p.Ser11Pro	missense_variant	Exon 1 of 7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.31T>C	p.Ser11Pro	missense_variant	Exon 1 of 8	1	NM_000133.4	ENSP00000218099.2
F9	ENST00000394090.2	c.31T>C	p.Ser11Pro	missense_variant	Exon 1 of 7	1		ENSP00000377650.2
F9	ENST00000479617.2	n.38T>C		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1097187 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 362641

African (AFR) AF: 0.00 AC: 0 AN: 26375

American (AMR) AF: 0.00 AC: 0 AN: 35190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19368

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

South Asian (SAS) AF: 0.00 AC: 0 AN: 54130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40523

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 841216

Other (OTH) AF: 0.00 AC: 0 AN: 46058

GnomAD4 genome Cov.: 24

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.7
DANN	Benign	0.94
DEOGEN2	Benign	0.28	T;.
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.46	N;N
PhyloP100		-0.48
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.42	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.21	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.0020	B;.
Vest4		0.30
MutPred		0.42		Gain of glycosylation at P12 (P = 0.0665);Gain of glycosylation at P12 (P = 0.0665);
MVP		0.63
MPC		0.092
ClinPred		0.045	T
GERP RS		-4.7
PromoterAI		-0.044	Neutral
Varity_R		0.11
gMVP		0.71
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs387906480; hg19: chrX-138612954;