rs137852407

Positions:

• chrX-154969360-A-G
• chrX-154969360-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5 PP3 PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.980T>C (p.Leu327Pro) variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). The variant has been reported in two probands with severe hemophilia A meeting phenotypic criteria for F8 in PMID:8644728 and 26897466. This missense variant has a REVEL score of 0.926 (>0.6). A pathogenic variant, Leu327Val, is reported at the same residue meeting PM5. In summary, based on the evidence available at this time, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PP3, PS4_Moderate, PM2_Supporting, PM5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA255086/MONDO:0010602/071

• Frequency: Genomes: not found (cov: 23)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 6.72

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 Likely_pathogenic. Variant got 6 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.980T>C	p.Leu327Pro	missense_variant	7/26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.980T>C	p.Leu327Pro	missense_variant	7/26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000647125.1	n.*856T>C		non_coding_transcript_exon_variant	8/14			ENSP00000496062.1
F8	ENST00000647125.1	n.*856T>C		3_prime_UTR_variant	8/14			ENSP00000496062.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	Sep 30, 2024	The c.980T>C (p.Leu327Pro) variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). The variant has been reported in two probands with severe hemophilia A meeting phenotypic criteria for F8 in PMID: 8644728 and 26897466. This missense variant has a REVEL score of 0.926 (>0.6). A pathogenic variant, Leu327Val, is reported at the same residue meeting PM5. In summary, based on the evidence available at this time, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PP3, PS4_Moderate, PM2_Supporting, PM5. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1995	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.72
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.93		Loss of stability (P = 0.0049);
MVP		1.0
MPC		2.1
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.99
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: rs137852407; hg19: chrX-154197635;