X-154837676-C-T

Position:

• chrX-154837676-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000132.4(F8):​c.6977G>A​(p.Arg2326Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000896 in 111,599 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2326G) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 23)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.17

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 18 ACMG points.

• PM1: In a domain F5/8 type C 2 (size 152) in uniprot entity FA8_HUMAN there are 31 pathogenic changes around while only 0 benign (100%) in NM_000132.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-154837676-C-T is Pathogenic according to our data. Variant chrX-154837676-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154837676-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.6977G>A	p.Arg2326Gln	missense_variant	26/26	ENST00000360256.9	NP_000123.1
F8	NM_019863.3	c.572G>A	p.Arg191Gln	missense_variant	5/5		NP_063916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.6977G>A	p.Arg2326Gln	missense_variant	26/26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000330287.10	c.572G>A	p.Arg191Gln	missense_variant	5/5	1		ENSP00000327895.6
F8	ENST00000644698.1	c.710G>A	p.Arg237Gln	missense_variant	6/6			ENSP00000495706.1

Frequencies

GnomAD3 genomes AF: 0.00000896 AC: 1 AN: 111599 Hom.: 0 Cov.: 23 AF XY: 0.0000296 AC XY: 1 AN XY: 33815

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000896 AC: 1 AN: 111599 Hom.: 0 Cov.: 23 AF XY: 0.0000296 AC XY: 1 AN XY: 33815

Gnomad4 AFR AF: 0.0000326

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	May 30, 1985	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2019	The F8 c.6977G>A; p.Arg2326Gln variant (rs137852360), also known as R2307Q, is reported in the literature in multiple individuals affected with mild to moderate hemophilia A (see link to FVIII Database and references therein). This variant is reported in ClinVar (Variation ID: 10126), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 2326 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses demonstrate destabilization of the protein (Spiegel 2004). Additionally, other amino acid substitutions at this codon (Gly, Leu, Pro) have been reported in individuals with moderate to severe hemophilia A and are considered pathogenic (see link to FVIII Database and references therein). Based on available information, this variant is considered to be pathogenic. References: Link to Factor VIII Gene Database: http://f8-db.eahad.org/index.php Spiegel PC et al. Surface-exposed hemophilic mutations across the factor VIII C2 domain have variable effects on stability and binding activities. J Biol Chem. 2004 Dec 17;279(51):53691-8. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 08, 2020	PS1, PM1, PP3, PP5. -

Hereditary factor IX deficiency disease Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

May 03, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;D;.
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	.;H;.
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.7	D;D;.
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.033	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.80
MutPred		0.99		.;Loss of catalytic residue at R2326 (P = 0.0392);.;
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.96
gMVP		1.0

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: rs137852360; hg19: chrX-154065951; COSMIC: COSV100371798; COSMIC: COSV100371798;