rs4149751

chrX-139562066-A-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000133.4(F9):c.1381A>C(p.Thr461Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 1,207,222 control chromosomes in the GnomAD database, including 3 homozygotes. There are 99 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., 43 hem., cov: 23)
  • Exomes 𝑓: 0.00018 (2 hom. 56 hem.)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.15

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 -18 ACMG points.

• PM1: In a chain Coagulation factor IXa heavy chain (size 234) in uniprot entity FA9_HUMAN there are 152 pathogenic changes around while only 9 benign (94%) in NM_000133.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0071655214).
• BP6: Variant X-139562066-A-C is Benign according to our data. Variant chrX-139562066-A-C is described in ClinVar as [Benign]. Clinvar id is 368004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00128 (143/111949) while in subpopulation AFR AF= 0.00416 (128/30806). AF 95% confidence interval is 0.00357. There are 1 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 42 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F9	NM_000133.4	c.1381A>C	p.Thr461Pro	missense_variant	8/8	ENST00000218099.7
F9	NM_001313913.2	c.1267A>C	p.Thr423Pro	missense_variant	7/7
F9	XM_005262397.5	c.1252A>C	p.Thr418Pro	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F9	ENST00000218099.7	c.1381A>C	p.Thr461Pro	missense_variant	8/8	1	NM_000133.4	P1
F9	ENST00000394090.2	c.1267A>C	p.Thr423Pro	missense_variant	7/7	1
F9	ENST00000643157.1	n.1723+325A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 140 AN: 111895 Hom.: 1 Cov.: 23 AF XY: 0.00123 AC XY: 42 AN XY: 34061

Gnomad AFR AF: 0.00407

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00104

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: 0.0000188

Gnomad OTH AF: 0.00200

GnomAD3 exomes AF: 0.000374 AC: 68 AN: 181976 Hom.: 0 AF XY: 0.000238 AC XY: 16 AN XY: 67262

Gnomad AFR exome AF: 0.00467

Gnomad AMR exome AF: 0.000256

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000723

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.000175 AC: 192 AN: 1095273 Hom.: 2 Cov.: 29 AF XY: 0.000155 AC XY: 56 AN XY: 360779

Gnomad4 AFR exome AF: 0.00547

Gnomad4 AMR exome AF: 0.000369

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000740

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000107

Gnomad4 OTH exome AF: 0.000413

GnomAD4 genome AF: 0.00128 AC: 143 AN: 111949 Hom.: 1 Cov.: 23 AF XY: 0.00126 AC XY: 43 AN XY: 34125

Gnomad4 AFR AF: 0.00416

Gnomad4 AMR AF: 0.00104

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00197

Alfa AF: 0.000140 Hom.: 7

Bravo AF: 0.00139

ESP6500AA AF: 0.00235 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000453 AC: 55

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor IX deficiency disease Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 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 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T;.
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.68	T;T
MetaRNN	Benign	0.0072	T;T
MetaSVM	Uncertain	0.055	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.90	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;.
Vest4		0.076
MVP		0.82
MPC		1.8
ClinPred		0.039	T
GERP RS		2.9
Varity_R		0.65
gMVP		0.94

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: rs4149751; hg19: chrX-138644225;