X-154966483-A-G

Variant names:

• chrX-154966483-A-G
• rs28933670
• NM_000132.4:c.1214T>C

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.1214T>C​(p.Ile405Thr) variant causes a missense change involving the alteration of a conserved nucleotide. 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. I405F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 7.42

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 domain Plastocyanin-like 3 (size 174) in uniprot entity FA8_HUMAN there are 44 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant X-154966483-A-G is Pathogenic according to our data. Variant chrX-154966483-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 3390360.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.1214T>C	p.Ile405Thr	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.1214T>C	p.Ile405Thr	missense_variant	Exon 8 of 26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000483822.2	n.34T>C		non_coding_transcript_exon_variant	Exon 1 of 2	3
F8	ENST00000647125.1	n.*1090T>C		non_coding_transcript_exon_variant	Exon 9 of 14			ENSP00000496062.1
F8	ENST00000647125	n.*1066T>C		3_prime_UTR_variant	Exon 9 of 14			ENSP00000496062.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:1

Dec 06, 2024

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The missense variant, NM_000132.3:c.1214T>C (p.Ile405Thr), is not reported in gnomAD v2.1.1 or v3 (PM2_Supporting). This variant has been reported in at least six male patients with moderate and severe Hemophilia A in the literature and meet phenotype criteria for F8 (PS4, PP4_Moderate, PMID: 29296726, 22103590, 24845853). The variant has a REVEL score of 0.981 (PP3, threshold >0.6). In summary, the variant meets criteria to be classified as likely pathogenic. c.1213T>C (p.Ile405Phe) is a variant at the same codon and is curated by the Coagulation Factor Deficiency VCEP to be likely pathogenic. c.1213T>C (p.Ile405Ser) is also a variant at the same codon and is curated by the Coagulation Factor Deficiency VCEP to be likely pathogenic so PM5 is met, however, the (p.Ile405Ser) was at VUS, so the (p.Ile405Phe) variant was used to apply PM5_Supporting to move it to LP. This variant reaches a classfication of Pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4, PP4_Moderate, PP3, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.90		Loss of sheet (P = 0.0357);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.91
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs28933670; hg19: chrX-154194758;