X-139530771-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000133.4(F9):c.7C>T(p.Arg3Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000024 in 1,207,866 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3H) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000023 (0 hom. 7 hem.)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.382

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012279302).
• BP6: Variant X-139530771-C-T is Benign according to our data. Variant chrX-139530771-C-T is described in ClinVar as [Benign]. Clinvar id is 765903.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F9	NM_000133.4	c.7C>T	p.Arg3Cys	missense_variant	1/8	ENST00000218099.7
F9	NM_001313913.2	c.7C>T	p.Arg3Cys	missense_variant	1/7
F9	XM_005262397.5	c.7C>T	p.Arg3Cys	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F9	ENST00000218099.7	c.7C>T	p.Arg3Cys	missense_variant	1/8	1	NM_000133.4	P1
F9	ENST00000394090.2	c.7C>T	p.Arg3Cys	missense_variant	1/7	1
F9	ENST00000479617.2	n.14C>T		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.0000356 AC: 4 AN: 112367 Hom.: 0 Cov.: 24 AF XY: 0.0000290 AC XY: 1 AN XY: 34531

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000946

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000839

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

GnomAD3 exomes AF: 0.0000874 AC: 16 AN: 183021 Hom.: 0 AF XY: 0.0000444 AC XY: 3 AN XY: 67635

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000650

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000490

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000228 AC: 25 AN: 1095443 Hom.: 0 Cov.: 29 AF XY: 0.0000194 AC XY: 7 AN XY: 361019

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000853

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000364

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000107

Gnomad4 OTH exome AF: 0.0000435

GnomAD4 genome AF: 0.0000356 AC: 4 AN: 112423 Hom.: 0 Cov.: 24 AF XY: 0.0000289 AC XY: 1 AN XY: 34597

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000945

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000842

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 26, 2023

- -

Hereditary factor IX deficiency disease Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 02, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	6.3
Dann	Benign	0.80
DEOGEN2	Benign	0.29	T;.
FATHMM_MKL	Benign	0.0041	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	-0.49	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.16
Sift	Benign	0.23	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.0	B;.
Vest4		0.13
MutPred		0.40		Gain of catalytic residue at M1 (P = 2e-04);Gain of catalytic residue at M1 (P = 2e-04);
MVP		0.37
MPC		0.099
ClinPred		0.010	T
GERP RS		-1.1
Varity_R		0.068
gMVP		0.75

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: rs766259893; hg19: chrX-138612930; COSMIC: COSV99496956;