rs137852364

Variant names:

• chrX-154966526-G-A
• rs137852364
• NM_000132.4:c.1171C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000132.4(F8):​c.1171C>T​(p.Arg391Cys) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R391H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.38
• Publications: 7 publications found

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]

F8 Gene-Disease associations (from GenCC):

• hemophilia A

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• mild hemophilia A

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• moderately severe hemophilia A

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• severe hemophilia A

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• symptomatic form of hemophilia A in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154966525-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 327 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 2.4669 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to hemophilia A, mild hemophilia A, symptomatic form of hemophilia A in female carriers, severe hemophilia A, moderately severe hemophilia A.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant X-154966526-G-A is Pathogenic according to our data. Variant chrX-154966526-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10125.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.1171C>T	p.Arg391Cys	missense_variant	Exon 8 of 26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.1171C>T	p.Arg391Cys	missense_variant	Exon 8 of 26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000647125.1	n.*1047C>T		non_coding_transcript_exon_variant	Exon 9 of 14			ENSP00000496062.1
F8	ENST00000647125.1	n.*1047C>T		3_prime_UTR_variant	Exon 9 of 14			ENSP00000496062.1
F8	ENST00000483822.2	n.-10C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000680

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:2

Apr 15, 1990

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 24, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: F8 c.1171C>T (p.Arg391Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1171C>T has been reported in the literature in multiple hemizygous males affected with Factor VIII Deficiency (Hemophilia A) and segregated with disease in at least one family (Shima_1989, Guo_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a ten fold decrease in thrombin activation (Shima_1989). The following publications have been ascertained in the context of this evaluation (PMID: 28056528, 2506948). ClinVar contains an entry for this variant (Variation ID: 10125). This variant is also known as p.Arg372Cys. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Dec 13, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F8 c.1171C>T; p.Arg391Cys variant (rs137852364), also known as Arg372Cys, is reported in the literature in multiple individuals affected with mild to severe hemophilia A (see F8 database and references therein, Feng 2021). This variant is reported in ClinVar (Variation ID: 10125) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (His, Leu, Gly, Pro) have been reported in individuals with hemophilia A and are considered pathogenic (F8 database). The arginine at codon 391 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.924). Based on available information, this variant is considered to be pathogenic. References: Link to F8 database: https://f8-db.eahad.org/index.php Feng Y et al. Mutation analysis in the F8 gene in 485 families with haemophilia A and prenatal diagnosis in China. Haemophilia. 2021 Jan;27(1):e88-e92.PMID: 33245802. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.73
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.88		Loss of MoRF binding (P = 0.0152);
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.83
gMVP		0.97
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137852364; hg19: chrX-154194801; COSMIC: COSV64270460; COSMIC: COSV64270460;