rs137852386

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000132.4(F8):​c.350T>G​(p.Leu117Arg) variant causes a missense change involving the alteration of a 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L117F) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

F8
NM_000132.4 missense

Scores

12
3
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.67
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 Pathogenic. Variant got 11 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 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 chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant X-154997011-A-C is Pathogenic according to our data. Variant chrX-154997011-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 10169.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-154997011-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
F8NM_000132.4 linkuse as main transcriptc.350T>G p.Leu117Arg missense_variant 3/26 ENST00000360256.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
F8ENST00000360256.9 linkuse as main transcriptc.350T>G p.Leu117Arg missense_variant 3/261 NM_000132.4 P1P00451-1
F8ENST00000423959.5 linkuse as main transcriptc.245T>G p.Leu82Arg missense_variant 3/63
F8ENST00000453950.1 linkuse as main transcriptc.332T>G p.Leu111Arg missense_variant 4/53
F8ENST00000647125.1 linkuse as main transcriptc.*136T>G 3_prime_UTR_variant, NMD_transcript_variant 3/14

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 1995- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Pathogenic
0.72
D
BayesDel_noAF
Pathogenic
0.79
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
D;D;D
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.84
T;T;T
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.3
M;.;.
MutationTaster
Benign
0.86
D
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-5.1
D;D;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0010
D;.;.
Polyphen
1.0
D;D;.
Vest4
0.96
MutPred
0.98
Gain of MoRF binding (P = 0.0211);.;.;
MVP
1.0
MPC
2.0
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.99
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

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

Other links and lift over

dbSNP: rs137852386; hg19: chrX-154225286; API