rs137852454

Variant names:

• chrX-154902053-T-C
• rs137852454
• NM_000132.4:c.6113A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-154902053-T-C
• chrX-154902053-T-G

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.6113A>G​(p.Asn2038Ser) variant causes a missense, splice region 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. 14/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: F8 NM_000132.4 missense, splice_region
• Scores: Splicing: ADA: 0.0008523
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.0850

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 domain Plastocyanin-like 6 (size 153) in uniprot entity FA8_HUMAN there are 32 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, 0.871
• PP5: Variant X-154902053-T-C is Pathogenic according to our data. Variant chrX-154902053-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 10305.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154902053-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.6113A>G	p.Asn2038Ser	missense_variant, splice_region_variant	Exon 19 of 26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.6113A>G	p.Asn2038Ser	missense_variant, splice_region_variant	Exon 19 of 26	1	NM_000132.4	ENSP00000353393.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000453

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:2

Jan 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 16, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: F8 c.6113A>G (p.Asn2038Ser) results in a conservative amino acid change located in the Coagulation factor 5/8 C-terminal domain (IPR000421) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' donor site. One predict the variant no significant impact on splicing. A functional study reported the variant did not affect normal protein features, but reduced splicing function (about 26% of normal activity, Donadon_2018). The variant was absent in 183122 control chromosomes. c.6113A>G has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A) (Donadon_2018, Eckhardt_2013). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 29170251, 23926300). ClinVar contains an entry for this variant (Variation ID: 10305). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	3.1
DANN	Benign	0.73
DEOGEN2	Benign	0.33	T
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.32	T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	0.55	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.25
Sift	Benign	0.097	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.64
MutPred		0.84		Gain of disorder (P = 0.0731);
MVP		0.85
MPC		0.65
ClinPred		0.082	T
GERP RS		0.79
Varity_R		0.17
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00085
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.23		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137852454; hg19: chrX-154130328;