rs6049

chrX-139541196-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000133.4(F9):c.391+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00773 in 1,127,094 control chromosomes in the GnomAD database, including 412 homozygotes. There are 2,222 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.036 (182 hom., 1042 hem., cov: 23)
  • Exomes 𝑓: 0.0046 (230 hom. 1180 hem.)
• Consequence: F9 NM_000133.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002569
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: 0.605

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant X-139541196-A-G is Benign according to our data. Variant chrX-139541196-A-G is described in ClinVar as [Benign]. Clinvar id is 367999.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F9	NM_000133.4	c.391+7A>G		splice_region_variant, intron_variant		ENST00000218099.7
F9	NM_001313913.2	c.277+3810A>G		intron_variant
F9	XM_005262397.5	c.391+7A>G		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F9	ENST00000218099.7	c.391+7A>G		splice_region_variant, intron_variant		1	NM_000133.4	P1
F9	ENST00000394090.2	c.277+3810A>G		intron_variant		1
F9	ENST00000479617.2	n.344+7A>G		splice_region_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0360 AC: 4020 AN: 111561 Hom.: 181 Cov.: 23 AF XY: 0.0304 AC XY: 1027 AN XY: 33771

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000328

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000715

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0109 AC: 1996 AN: 182372 Hom.: 98 AF XY: 0.00696 AC XY: 467 AN XY: 67138

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.00538

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000724

Gnomad SAS exome AF: 0.000158

Gnomad FIN exome AF: 0.000944

Gnomad NFE exome AF: 0.000418

Gnomad OTH exome AF: 0.00803

GnomAD4 exome AF: 0.00461 AC: 4679 AN: 1015480 Hom.: 230 Cov.: 20 AF XY: 0.00398 AC XY: 1180 AN XY: 296634

Gnomad4 AFR exome AF: 0.145

Gnomad4 AMR exome AF: 0.00658

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.000731

Gnomad4 NFE exome AF: 0.000363

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.0362 AC: 4038 AN: 111614 Hom.: 182 Cov.: 23 AF XY: 0.0308 AC XY: 1042 AN XY: 33834

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000328

Gnomad4 NFE AF: 0.000715

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0322 Hom.: 143

Bravo AF: 0.0420

EpiCase AF: 0.000819

EpiControl AF: 0.000833

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary factor IX deficiency disease Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, reviewed by expert panel	curation	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	Feb 09, 2024	The c.391+7A>G variant is reported at an MAF of 0.1296 (2458/18960 alleles) in the African/African-American population in gnomAD v2.1.1 with 620 hemizygotes and 123 homozygotes, meeting BA1 criteria of MAF > 0.0000556. SpliceAI predicts WT canonical donor loss at -7bp with a delta score of 0.05; however, does not meet criteria for PP3 or BP4. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: BA1. -

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 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	3.5
Dann	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.050		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: rs6049; hg19: chrX-138623355;