rs137852464

chrX-154863125-G-A

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.6532C>T(p.Arg2178Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000365 in 1,097,251 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2178L) has been classified 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 criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.91

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 hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 uncertain 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 chrX-154863124-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant X-154863125-G-A is Pathogenic according to our data. Variant chrX-154863125-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154863125-G-A is described in Lovd as [Likely_pathogenic]. Variant chrX-154863125-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F8	NM_000132.4	c.6532C>T	p.Arg2178Cys	missense_variant	23/26	ENST00000360256.9
F8	NM_019863.3	c.127C>T	p.Arg43Cys	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.6532C>T	p.Arg2178Cys	missense_variant	23/26	1	NM_000132.4	P1
F8	ENST00000330287.10	c.127C>T	p.Arg43Cys	missense_variant	2/5	1
F8	ENST00000644698.1	c.265C>T	p.Arg89Cys	missense_variant	3/6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000365 AC: 4 AN: 1097251 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362621

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000357

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000198 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 27, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	Jun 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Mar 10, 2023	The hemizygous, maternally inherited c.6532C>T, p.(Arg2178Cys) variant (also called R2159C, or p.Arg2159Cys) identified in the F8 gene of this fetus has been reported in many affected individuals and is typically associated with mild hemophilia A [PMID:1924291, 11754115, 17445092, 21771207, others]. Decreased Factor VIII activity has been reported in a male with the c.6532C>T, p.(Arg2178Cys) variant [PMID:1924291]. This variant is reported in ClinVar as Pathogenic (VarID:10318; 1 star, 3 submissions, no conflicts), and two different amino acid changes at the same amino acid position, p.Arg2178Leu (VarID:10314) and p.Arg2178His (VarID:10319) are also reported as Likely Pathogenic/Pathogenic. In silico algorithm REVEL predicts this variant to be damaging to protein function (Score: 0.875). Given the available evidence the hemizygous, maternally inherited c.6532C>T, p.(Arg2178Cys) variant identified in the F8 gene is reported as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 13, 2022

The F8 c.6532C>T; p.Arg2178Cys variant (rs137852464), also known as R2159C, is reported in the literature in multiple individuals and families affected with mild to moderate hemophilia A (see link to FVIII database and references therein, Markoff 2009). This variant is also reported in ClinVar (Variation ID: 10318). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 2178 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.875). Additionally, other amino acid substitutions at this codon (Leu, His, Lys) have been reported in individuals with mild hemophilia A and are considered pathogenic (FVIII database, Markoff 2009). Based on available information, the p.Arg2178Cys variant is considered to be pathogenic. References: Link to FVIII database: http://www.factorviii-db.org/ Markoff A et al. Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function. Haemophilia. 2009 Jul;15(4):932-41. PMID: 19473423 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.1	D;D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.029	D;D;.
Sift4G	Benign	0.075	T;D;.
Polyphen		1.0	.;D;.
Vest4		0.40
MutPred		0.93		.;Loss of MoRF binding (P = 0.0358);.;
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137852464; hg19: chrX-154091400; COSMIC: COSV57704793;