NM_000133.4:c.391+10T>G

Variant names:

• chrX-139541199-T-G
• rs375734226
• NM_000133.4:c.391+10T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000133.4(F9):​c.391+10T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,100,580 control chromosomes in the GnomAD database, including 13 homozygotes. There are 370 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., 31 hem., cov: 23)
  • Exomes 𝑓: 0.0011 (13 hom. 339 hem.)
• Consequence: F9 NM_000133.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.259
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-139541199-T-G is Benign according to our data. Variant chrX-139541199-T-G is described in ClinVar as Benign. ClinVar VariationId is 288250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00111 (124/111774) while in subpopulation AMR AF = 0.000573 (6/10467). AF 95% confidence interval is 0.000249. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 31 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000133.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F9	NM_000133.4	MANE Select	c.391+10T>G		intron	N/A	NP_000124.1
	F9	NM_001313913.2		c.277+3813T>G		intron	N/A	NP_001300842.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F9	ENST00000218099.7	TSL:1 MANE Select	c.391+10T>G		intron	N/A	ENSP00000218099.2
	F9	ENST00000394090.2	TSL:1	c.277+3813T>G		intron	N/A	ENSP00000377650.2
	F9	ENST00000479617.2	TSL:5	n.344+10T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 124 AN: 111774 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000573

Gnomad ASJ AF: 0.0398

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000169

Gnomad OTH AF: 0.000665

GnomAD2 exomes AF: 0.00225 AC: 410 AN: 182149 AF XY: 0.00208

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.0459

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000407

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00110 AC: 1090 AN: 988806 Hom.: 13 Cov.: 18 AF XY: 0.00122 AC XY: 339 AN XY: 278328

African (AFR) AF: 0.00 AC: 0 AN: 24177

American (AMR) AF: 0.000905 AC: 31 AN: 34243

Ashkenazi Jewish (ASJ) AF: 0.0456 AC: 812 AN: 17788

East Asian (EAS) AF: 0.00 AC: 0 AN: 28106

South Asian (SAS) AF: 0.00 AC: 0 AN: 51685

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38136

Middle Eastern (MID) AF: 0.000266 AC: 1 AN: 3766

European-Non Finnish (NFE) AF: 0.000164 AC: 123 AN: 749362

Other (OTH) AF: 0.00296 AC: 123 AN: 41543

GnomAD4 genome AF: 0.00111 AC: 124 AN: 111774 Hom.: 0 Cov.: 23 AF XY: 0.000913 AC XY: 31 AN XY: 33956

African (AFR) AF: 0.0000974 AC: 3 AN: 30791

American (AMR) AF: 0.000573 AC: 6 AN: 10467

Ashkenazi Jewish (ASJ) AF: 0.0398 AC: 105 AN: 2636

East Asian (EAS) AF: 0.00 AC: 0 AN: 3545

South Asian (SAS) AF: 0.00 AC: 0 AN: 2659

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6079

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.000169 AC: 9 AN: 53164

Other (OTH) AF: 0.000665 AC: 1 AN: 1504

Alfa AF: 0.00626 Hom.: 40

Bravo AF: 0.00134

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary factor IX deficiency disease (1)
-	-	1	Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.17
DANN	Benign	0.64
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs375734226; hg19: chrX-138623358;