X-154987242-T-G

Variant names:

• chrX-154987242-T-G
• rs137852396
• NM_000132.4:c.665A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_000132.4(F8):​c.665A>C​(p.Asp222Ala) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.22

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 8 ACMG points.

• PM1: In a strand (size 9) 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, 0.931
• PP5: Variant X-154987242-T-G is Pathogenic according to our data. Variant chrX-154987242-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1330641.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.665A>C	p.Asp222Ala	missense_variant	Exon 5 of 26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.665A>C	p.Asp222Ala	missense_variant	Exon 5 of 26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000423959.5	c.560A>C	p.Asp187Ala	missense_variant	Exon 5 of 6	3		ENSP00000409446.1
F8	ENST00000647125.1	n.*451A>C		non_coding_transcript_exon_variant	Exon 5 of 14			ENSP00000496062.1
F8	ENST00000647125	n.*427A>C		3_prime_UTR_variant	Exon 5 of 14			ENSP00000496062.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000151

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:1

Nov 12, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F8 c.665A>C; p.Asp222Ala variant (rs137852396), also known as Asp203Ala, is reported in the literature in individuals affected with hemophilia A (see link to FVIII database, Johnsen 2017). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The aspartate at codon 222 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.883). Additionally, other variants at this codon (c.665A>T; p.Asp222Val, c.665A>G; p.Asp222Gly) have been reported in individuals with hemophilia A (see link to FVIII database and references therein, Bogdanova 2007, Johnsen 2017). Based on available information, this variant is considered to be likely pathogenic. References: Link to FVIII database: https://f8-db.eahad.org/index.php Bogdanova N et al. Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A. Hum Mutat. 2007 Jan;28(1):54-60. PMID: 16972227. Johnsen JM et al. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. Blood Adv. 2017 May 18;1(13):824-834. PMID: 29296726. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;D
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.81	T;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;.
Polyphen		1.0	D;.
Vest4		0.46
MutPred		0.71		Loss of sheet (P = 0.0817);.;
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.91
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: rs137852396; hg19: chrX-154215517;