rs6048

Variant names:

• chrX-139551121-A-G
• rs6048
• NM_000133.4:c.580A>G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: The c.580A>G (p.Thr194Ala) variant is reported at an MAF of 0.3026 (27985/92495 alleles) in the non-Finnish European population in gnomAD v2.1.1 with 2609 homozygotes and 10667 hemizygotes, meeting BA1 criteria of MAF > 0.0000556. Note that gnomAD v3.1.1 reports a frequency of 0.3041 in the NFE population, with 1859 homozygotes and 4024 hemizygotes. This missense variant has a REVEL score of 0.255 (<0.3) and SpliceAI predicts no impact on splicing, with a score of 0.0, meeting BP4 criteria. 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, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA121125/MONDO:0010604/080

• Frequency:
  • Genomes: 𝑓 0.22 (2307 hom., 7148 hem., cov: 23)
  • Exomes 𝑓: 0.27 (29445 hom. 98085 hem.)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Benign reviewed by expert panel B:11
• Conservation: PhyloP100: 0.555

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 -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F9	NM_000133.4	c.580A>G	p.Thr194Ala	missense_variant	Exon 6 of 8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.466A>G	p.Thr156Ala	missense_variant	Exon 5 of 7		NP_001300842.1
F9	XM_005262397.5	c.451A>G	p.Thr151Ala	missense_variant	Exon 5 of 7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.580A>G	p.Thr194Ala	missense_variant	Exon 6 of 8	1	NM_000133.4	ENSP00000218099.2
F9	ENST00000394090.2	c.466A>G	p.Thr156Ala	missense_variant	Exon 5 of 7	1		ENSP00000377650.2
F9	ENST00000643157.1	n.1247A>G		non_coding_transcript_exon_variant	Exon 4 of 7

Frequencies

GnomAD3 genomes AF: 0.223 AC: 24831 AN: 111270 Hom.: 2310 Cov.: 23 AF XY: 0.213 AC XY: 7142 AN XY: 33494

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.00392

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.184

GnomAD3 exomes AF: 0.217 AC: 39784 AN: 183245 Hom.: 3235 AF XY: 0.225 AC XY: 15221 AN XY: 67697

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.00253

Gnomad SAS exome AF: 0.175

Gnomad FIN exome AF: 0.266

Gnomad NFE exome AF: 0.303

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.273 AC: 299272 AN: 1097623 Hom.: 29445 Cov.: 31 AF XY: 0.270 AC XY: 98085 AN XY: 363129

Gnomad4 AFR exome AF: 0.126

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.240

Gnomad4 EAS exome AF: 0.00136

Gnomad4 SAS exome AF: 0.177

Gnomad4 FIN exome AF: 0.271

Gnomad4 NFE exome AF: 0.302

Gnomad4 OTH exome AF: 0.251

GnomAD4 genome AF: 0.223 AC: 24829 AN: 111325 Hom.: 2307 Cov.: 23 AF XY: 0.213 AC XY: 7148 AN XY: 33559

Gnomad4 AFR AF: 0.132

Gnomad4 AMR AF: 0.148

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.00422

Gnomad4 SAS AF: 0.164

Gnomad4 FIN AF: 0.262

Gnomad4 NFE AF: 0.304

Gnomad4 OTH AF: 0.181

Alfa AF: 0.278 Hom.: 26612

Bravo AF: 0.207

TwinsUK AF: 0.299 AC: 1107

ALSPAC AF: 0.300 AC: 867

ESP6500AA AF: 0.124 AC: 474

ESP6500EA AF: 0.298 AC: 2007

ExAC AF: 0.224 AC: 27172

EpiCase AF: 0.293

EpiControl AF: 0.302

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary factor IX deficiency disease Benign:4

Feb 09, 2024

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.580A>G (p.Thr194Ala) variant is reported at an MAF of 0.3026 (27985/92495 alleles) in the non-Finnish European population in gnomAD v2.1.1 with 2609 homozygotes and 10667 hemizygotes, meeting BA1 criteria of MAF > 0.0000556. Note that gnomAD v3.1.1 reports a frequency of 0.3041 in the NFE population, with 1859 homozygotes and 4024 hemizygotes. This missense variant has a REVEL score of 0.255 (<0.3) and SpliceAI predicts no impact on splicing, with a score of 0.0, meeting BP4 criteria. 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, BP4. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Feb 12, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 25, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Deep venous thrombosis, protection against Benign:1

May 01, 2009

OMIM

Significance: protective

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Thrombophilia, X-linked, due to factor 9 defect Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.53
DANN	Benign	0.39
DEOGEN2	Benign	0.38	T;.
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.32	T;T
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.92	N;N
REVEL	Benign	0.26
Sift	Benign	0.65	T;T
Sift4G	Benign	0.74	T;T
Polyphen		0.0	B;.
Vest4		0.064
MPC		0.62
ClinPred		0.0019	T
GERP RS		1.2
Varity_R		0.059
gMVP		0.93

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: rs6048; hg19: chrX-138633280; COSMIC: COSV54379523; COSMIC: COSV54379523;