X-154953991-G-C

Position:

• chrX-154953991-G-C

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.1804C>G​(p.Arg602Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,097,407 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes 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: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 1 hem.)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.16

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 4 (size 147) in uniprot entity FA8_HUMAN there are 41 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-154953991-G-C is Pathogenic according to our data. Variant chrX-154953991-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 627259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154953991-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.1804C>G	p.Arg602Gly	missense_variant	12/26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.1804C>G	p.Arg602Gly	missense_variant	12/26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000647125.1	n.*1680C>G		non_coding_transcript_exon_variant	13/14			ENSP00000496062.1
F8	ENST00000647125.1	n.*1680C>G		3_prime_UTR_variant	13/14			ENSP00000496062.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1097407 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362779

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: 0.00000475

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 08, 2019	The F8 c.1804C>G (p.Arg602Gly) missense variant that has been reported in at least two studies and is identified in a hemizygous state in at least eight individuals with mild hemophilia A (Bowyer et al. 2013; Beskorovainaya et al. 2019). Control data are unavailable for this variant, which is not found in in the Genome Aggregation Database despite good sequence coverage, so the variant is presumed to be rare. Based on the prevalence of the variant in affected individuals compared to controls, absence from population frequency databases, and location in a functional domain in a variant hotspot, the p.Arg602Gly variant is classified as likely pathogenic for hemophilia A. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 10, 2023	Variant summary: F8 c.1804C>G (p.Arg602Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183429 control chromosomes. c.1804C>G has been reported in the literature in multiple individuals affected with mild Factor VIII Deficiency (Hemophilia A) (example, Hill_2005, Green_2008, Miller_2012, Eckhardt_2013, Downes_2019). 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: 31064749, 23926300, 18691168, 15810915, 22103590). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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	Benign	0.14
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.015	D
Polyphen		0.14	B
Vest4		0.80
MutPred		0.83		Gain of loop (P = 0.1069);
MVP		1.0
MPC		1.1
ClinPred		0.86	D
GERP RS		3.4
Varity_R		0.64
gMVP		0.92

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: rs137852424; hg19: chrX-154182266;