X-139530815-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000133.4(F9):c.51C>T(p.Ile17=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,209,372 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 39 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., 5 hem., cov: 24)
  • Exomes 𝑓: 0.00013 (0 hom. 34 hem.)
• Consequence: F9 NM_000133.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: 0.121

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant X-139530815-C-T is Benign according to our data. Variant chrX-139530815-C-T is described in ClinVar as [Benign]. Clinvar id is 697610.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=0.121 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00013 (143/1096890) while in subpopulation AMR AF= 0.00389 (137/35192). AF 95% confidence interval is 0.00336. There are 0 homozygotes in gnomad4_exome. There are 34 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F9	NM_000133.4	c.51C>T	p.Ile17=	synonymous_variant	1/8	ENST00000218099.7
F9	NM_001313913.2	c.51C>T	p.Ile17=	synonymous_variant	1/7
F9	XM_005262397.5	c.51C>T	p.Ile17=	synonymous_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F9	ENST00000218099.7	c.51C>T	p.Ile17=	synonymous_variant	1/8	1	NM_000133.4	P1
F9	ENST00000394090.2	c.51C>T	p.Ile17=	synonymous_variant	1/7	1
F9	ENST00000479617.2	n.58C>T		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.000107 AC: 12 AN: 112482 Hom.: 0 Cov.: 24 AF XY: 0.000144 AC XY: 5 AN XY: 34650

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00114

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

GnomAD3 exomes AF: 0.000677 AC: 124 AN: 183099 Hom.: 0 AF XY: 0.000443 AC XY: 30 AN XY: 67691

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00453

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000130 AC: 143 AN: 1096890 Hom.: 0 Cov.: 29 AF XY: 0.0000938 AC XY: 34 AN XY: 362368

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00389

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: 0.00000357

Gnomad4 OTH exome AF: 0.0000651

GnomAD4 genome AF: 0.000107 AC: 12 AN: 112482 Hom.: 0 Cov.: 24 AF XY: 0.000144 AC XY: 5 AN XY: 34650

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00114

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: 0.000355

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary factor IX deficiency disease Benign:2

Benign, reviewed by expert panel	curation	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	Feb 09, 2024	The NM_000133.4:c.51C>T (p.Ile17=) synonymous variant is reported at a high MAF of 0.004462 (125/28017 alleles with 31 hemizygotes) in the Latino population of gnomAD v2.1.1, meeting the BA1 cut-off of >/= 0.0000556. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency VCEP for F9: BA1. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 11, 2020	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	9.2
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs774612303; hg19: chrX-138612974;