rs137852368

Positions:

• chrX-154966634-G-A
• chrX-154966634-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS4 PVS1 PP4_Moderate PP1 PM2_Supporting PS2_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1063C>T (p.Arg355Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon in exon 8/26 and expected to result in nonsense-mediated mRNA decay, which meets PVS1 criteria. At least 20 probands from the literature reviewed below are reported to be hemizygous for the Arg355Ter variant, with severe Hemophilia A (FVIII:C <1%), which meets the PP4_Moderate and PS4_Very strong criteria. Inhibitors are reported in a few of these patients. One de novo occurrence without confirmation of maternity or paternity and an expected severe phenotype is reported in PMID:29381227, which meets the PS2_Moderate criteria. Two siblings in one family in PMID:15996930 are noted to have severe HA and the Arg355Ter variant, which meets PP1 criteria. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PVS1, PS4_Very Strong, PP4_Moderate, PS2_Moderate, PP1, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA255031/MONDO:0010602/071

• Frequency: Genomes: not found (cov: 22)
• Consequence: F8 NM_000132.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 0.357

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.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.1063C>T	p.Arg355Ter	stop_gained	8/26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.1063C>T	p.Arg355Ter	stop_gained	8/26	1	NM_000132.4	ENSP00000353393	P1
F8	ENST00000647125.1	c.*939C>T		3_prime_UTR_variant, NMD_transcript_variant	9/14			ENSP00000496062

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183153 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67683

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 21, 2021	The F8 c.1063C>T; p.Arg355Ter variant (rs137852368) is reported in numerous individuals with severe hemophilia A (see Factor VIII Variant Database and references therein), and is also reported in ClinVar (Variation ID: 10139). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Factor VIII Variant Database: http://f8-db.eahad.org/advance_search_results.php -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 30, 1985	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	Feb 02, 2024	The c.1063C>T (p.Arg355Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon in exon 8/26 and expected to result in nonsense-mediated mRNA decay, which meets PVS1 criteria. At least 20 probands from the literature reviewed below are reported to be hemizygous for the Arg355Ter variant, with severe Hemophilia A (FVIII:C <1%), which meets the PP4_Moderate and PS4_Very strong criteria. Inhibitors are reported in a few of these patients. One de novo occurrence without confirmation of maternity or paternity and an expected severe phenotype is reported in PMID: 29381227, which meets the PS2_Moderate criteria. Two siblings in one family in PMID: 15996930 are noted to have severe HA and the Arg355Ter variant, which meets PP1 criteria. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PVS1, PS4_Very Strong, PP4_Moderate, PS2_Moderate, PP1, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic (ClinVar ID: VCV000010139 / PMID: 3137981). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.070	N
MutationTaster	Benign	1.0	A
Vest4		0.86
GERP RS		3.2

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: rs137852368; hg19: chrX-154194909;