chrX-154966634-G-A

Variant names:

• chrX-154966634-G-A
• rs137852368
• NM_000132.4:c.1063C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS4 PS2_Moderate PP1 PVS1 PP4_Moderate PM2_Supporting

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
• Publications: 8 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 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000132.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	NM_000132.4	MANE Select	c.1063C>T	p.Arg355*	stop_gained	Exon 8 of 26	NP_000123.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	ENST00000360256.9	TSL:1 MANE Select	c.1063C>T	p.Arg355*	stop_gained	Exon 8 of 26	ENSP00000353393.4
	F8	ENST00000647125.1		n.*939C>T		non_coding_transcript_exon	Exon 9 of 14	ENSP00000496062.1
	F8	ENST00000647125.1		n.*939C>T		3_prime_UTR	Exon 9 of 14	ENSP00000496062.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183153 AF XY: 0.00

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 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

Alfa AF: 0.00 Hom.: 0

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:3

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 02, 2024

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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.

May 30, 1985

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:1

Dec 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.36
Vest4		0.86
GERP RS		3.2
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137852368; hg19: chrX-154194909;