X-155022464-T-C

Variant names:

• chrX-155022464-T-C
• rs137852378
• NM_000132.4:c.89A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E30V) has been classified as Pathogenic.

• 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
• Publications: 0 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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 chrX-155022464-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10154.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 327 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 2.4669 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to hemophilia A, mild hemophilia A, symptomatic form of hemophilia A in female carriers, severe hemophilia A, moderately severe hemophilia A.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.89A>G	p.Glu30Gly	missense_variant	Exon 1 of 26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.89A>G	p.Glu30Gly	missense_variant	Exon 1 of 26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000453950.1	c.71A>G	p.Glu24Gly	missense_variant	Exon 2 of 5	3		ENSP00000389153.1
F8	ENST00000647125.1	n.89A>G		non_coding_transcript_exon_variant	Exon 1 of 14			ENSP00000496062.1
F8	ENST00000423959.5	c.38+4316A>G		intron_variant	Intron 1 of 5	3		ENSP00000409446.1

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

Aug 19, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.
PhyloP100		2.1
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;.
Vest4		0.38
ClinPred		0.99	D
GERP RS		4.0
PromoterAI		-0.044	Neutral
Varity_R		0.45
gMVP		0.99
Mutation Taster		=2/98	disease causing

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: rs137852378; hg19: chrX-154250739;