chrX-154957073-G-A

Position:

• chrX-154957073-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000132.4(F8):​c.1636C>T​(p.Arg546Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,302 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.35

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant X-154957073-G-A is Pathogenic according to our data. Variant chrX-154957073-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154957073-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.1636C>T	p.Arg546Trp	missense_variant	11/26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.1636C>T	p.Arg546Trp	missense_variant	11/26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000647125.1	n.*1512C>T		non_coding_transcript_exon_variant	12/14			ENSP00000496062.1
F8	ENST00000647125.1	n.*1512C>T		3_prime_UTR_variant	12/14			ENSP00000496062.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096302 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 361710

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Alfa AF: 0.0000570 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010222 / PMID: 1924291). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 04, 2021	ACMG classification criteria: PS4 strong, PM2 moderate, PP3 supporting, PP4 supporting -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 03, 2024	Variant summary: F8 c.1636C>T (p.Arg546Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183428 control chromosomes (gnomAD). c.1636C>T has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A; e.g. Silva Pinto_2012, Rosset_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21645180, 23711237). ClinVar contains an entry for this variant (Variation ID: 10222). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 09, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 16, 2022	The F8 c.1636C>T; p.Arg546Trp variant (rs137852416), also known as Arg527Trp, is reported in the literature in individuals with mild to moderate hemophilia A (Bogdanova 2007, Schwaab 1995, Factor VIII database and references therein). This variant is reported in more than 80 affected individuals in the Factor VIII database with clotting activity measurements ranging from 2.3% to 42% of normal. This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 546 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.837). Based on available information, this variant is considered to be pathogenic. References: Factor VIII database: http://f8-db.eahad.org Bogdanova N et al. Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A. Hum Mutat. 2007 Jan;28(1):54-60. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2024	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; Also known as p.(R527W); This variant is associated with the following publications: (PMID: 18691168, 9439662, 34889362, 30997536, 1924291, 32224444, 7728145, 19473423, 31064749, 8547094, 7794769, 25212677, 34708896, 9886318, 11857744, 10404764, 8449505, 9029040, 11748850, 12871415, 16972227, 24452774, 16128892, 16769589, 17445092, 18540892, 34275734, 18565236) -

Hereditary factor IX deficiency disease Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.77
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.94
gMVP		0.96

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: rs137852416; hg19: chrX-154185348; COSMIC: COSV100812232;