X-155022464-T-C

Position:

• chrX-155022464-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000132.4(F8):​c.89A>G​(p.Glu30Gly) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.10

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.

• PM1: In a strand (size 12) in uniprot entity FA8_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000132.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.89A>G	p.Glu30Gly	missense_variant	1/26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.89A>G	p.Glu30Gly	missense_variant	1/26	1	NM_000132.4	ENSP00000353393	P1
F8	ENST00000453950.1	c.71A>G	p.Glu24Gly	missense_variant	2/5	3		ENSP00000389153
F8	ENST00000423959.5	c.38+4316A>G		intron_variant		3		ENSP00000409446
F8	ENST00000647125.1	c.89A>G	p.Glu30Gly	missense_variant, NMD_transcript_variant	1/14			ENSP00000496062

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary factor VIII deficiency disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 19, 2021

The F8 c.89A>G; p.Glu30Gly variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other variants at this codon (c.88G>A, p.Glu30Lys; c.89A>T, p.Glu30Val) have been reported in individuals with mild to moderate hemophilia A and are considered pathogenic (see F8 database and references therein, Abdul-Ghafar 2010). The glutamic acid at codon 30 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.83). However, given the lack of clinical and functional data, the significance of the p.Glu30Gly variant is uncertain at this time. References: Link to F8 database and references therein : https://f8-db.eahad.org/index.php Abdul-Ghafar A et al. Ten novel factor VIII (F8C) mutations in eighteen haemophilia A families detected in Singapore. Haemophilia. 2010 May;16(3):551-3. PMID: 20028422. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;T
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.83
Sift	Benign	0.053	T;D
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.38
MutPred		0.74		Gain of catalytic residue at S32 (P = 0.0953);.;
MVP		0.99
MPC		1.7
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.45
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-154250739;