rs6049

Positions:

chrX-139541196-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10529780/MONDO:0010604/080

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:6

Conservation

PhyloP100: 0.605

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
F9	NM_000133.4 linkuse as main transcript	c.391+7A>G	splice_region_variant, intron_variant	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2 linkuse as main transcript	c.277+3810A>G	intron_variant		NP_001300842.1
F9	XM_005262397.5 linkuse as main transcript	c.391+7A>G	splice_region_variant, intron_variant		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7 linkuse as main transcript	c.391+7A>G	splice_region_variant, intron_variant	1	NM_000133.4	ENSP00000218099	P1	P00740-1
F9	ENST00000394090.2 linkuse as main transcript	c.277+3810A>G	intron_variant	1		ENSP00000377650		P00740-2
F9	ENST00000479617.2 linkuse as main transcript	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.:

AF XY:

0.0304

AC XY:

1027

AN XY:

33771

show subpopulations

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.:

AF XY:

0.00696

AC XY:

467

AN XY:

67138

show subpopulations

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.:

AF XY:

0.00398

AC XY:

1180

AN XY:

296634

show subpopulations

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.:

AF XY:

0.0308

AC XY:

1042

AN XY:

33834

show subpopulations

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:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary factor IX deficiency disease

Benign:3

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. -
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	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 21, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over