chrX-154997095-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_000132.4(F8):​c.266G>T​(p.Gly89Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G89D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

F8
NM_000132.4 missense, splice_region

Scores

12
4
1
Splicing: ADA: 0.9989
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.47
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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-154999479-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3766866.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
F8NM_000132.4 linkc.266G>T p.Gly89Val missense_variant, splice_region_variant Exon 3 of 26 ENST00000360256.9 NP_000123.1 P00451-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
F8ENST00000360256.9 linkc.266G>T p.Gly89Val missense_variant, splice_region_variant Exon 3 of 26 1 NM_000132.4 ENSP00000353393.4 P00451-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
23
Bravo
AF:
0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.66
D
BayesDel_noAF
Pathogenic
0.71
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.96
D;T;D
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.89
D;D;D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.94
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.7
H;.;.
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-8.3
D;D;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;.;.
Polyphen
1.0
D;D;.
Vest4
0.89
MutPred
0.76
Loss of catalytic residue at M88 (P = 0.1769);.;.;
MVP
0.99
MPC
1.9
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.99
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.92
SpliceAI score (max)
0.47
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.47
Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137852380; hg19: chrX-154225370; API