X-154969459-G-C

Variant names:

• chrX-154969459-G-C
• NM_000132.4:c.881C>G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000132.4(F8):​c.881C>G​(p.Thr294Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.49

Genes affected

F8 (HGNC:3546): (coagulation factor VIII) This gene encodes coagulation factor VIII, which participates in the intrinsic pathway of blood coagulation; factor VIII is a cofactor for factor IXa which, in the presence of Ca+2 and phospholipids, converts factor X to the activated form Xa. This gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity. Defects in this gene results in hemophilia A, a common recessive X-linked coagulation disorder. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a domain Plastocyanin-like 2 (size 142) in uniprot entity FA8_HUMAN there are 34 pathogenic changes around while only 0 benign (100%) in NM_000132.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant X-154969459-G-C is Pathogenic according to our data. Variant chrX-154969459-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2428659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.881C>G	p.Thr294Arg	missense_variant	Exon 7 of 26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.881C>G	p.Thr294Arg	missense_variant	Exon 7 of 26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000647125.1	n.*757C>G		non_coding_transcript_exon_variant	Exon 8 of 14			ENSP00000496062.1
F8	ENST00000647125	n.*733C>G		3_prime_UTR_variant	Exon 8 of 14			ENSP00000496062.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Aug 10, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29296726, 35770352, 28056528, 32897612, 8547094) -

May 19, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F8 c.881C>G; p.Thr294Arg variant is reported in the literature in an individual affected with hemophilia (Johnsen 2017). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 294 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.872). Additionally, another missense variant in the same codon, c.881C>T; p.Thr294Ile, has been described in several affected individuals and is considered pathogenic (Hua 2010, Schwaab 1995, Sirocova 2009). Based on available information, this variant is classified as likely pathogenic. References: Hua BL et al. Identification of seven novel mutations in the factor VIII gene in 18 unrelated Chinese patients with hemophilia A. Chin Med J (Engl). 2010 Feb 5;123(3):305-10. PMID: 20193250. Johnsen JM et al. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. Blood Adv. 2017 May 18;1(13):824-834. PMID: 29296726. Schwaab R et al. Characterization of mutations within the factor VIII gene of 73 unrelated mild and moderate haemophiliacs. Br J Haematol. 1995 Oct;91(2):458-64. PMID: 8547094. Sirocova N et al. Factor VIII mutations in 42 Moldovan haemophilia A families, including 12 that are novel. Haemophilia. 2009 Jul;15(4):942-51. PMID: 19473408. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.2	M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.87
Sift	Benign	0.037	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.85		Gain of methylation at T294 (P = 0.0583);
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.95
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-154197734;