rs137852379
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP5_ModerateBP4BS2
The NM_000132.4(F8):c.121G>T(p.Gly41Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000405 in 1,208,566 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.000045 ( 0 hom., 1 hem., cov: 23)
Exomes 𝑓: 0.000040 ( 0 hom. 15 hem. )
Consequence
F8
NM_000132.4 missense
NM_000132.4 missense
Scores
1
6
10
Clinical Significance
Conservation
PhyloP100: -0.847
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_benign. Variant got -3 ACMG points.
PP5
Variant X-155022432-C-A is Pathogenic according to our data. Variant chrX-155022432-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 10156.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-155022432-C-A is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.17058894). . Strength limited to SUPPORTING due to the PP5.
BS2
High Hemizygotes in GnomAdExome4 at 15 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
F8 | NM_000132.4 | c.121G>T | p.Gly41Cys | missense_variant | 1/26 | ENST00000360256.9 | NP_000123.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
F8 | ENST00000360256.9 | c.121G>T | p.Gly41Cys | missense_variant | 1/26 | 1 | NM_000132.4 | ENSP00000353393.4 | ||
F8 | ENST00000453950.1 | c.103G>T | p.Gly35Cys | missense_variant | 2/5 | 3 | ENSP00000389153.1 | |||
F8 | ENST00000423959.5 | c.38+4348G>T | intron_variant | 3 | ENSP00000409446.1 | |||||
F8 | ENST00000647125.1 | n.121G>T | splice_region_variant, non_coding_transcript_exon_variant | 1/14 | ENSP00000496062.1 |
Frequencies
GnomAD3 genomes AF: 0.0000451 AC: 5AN: 110913Hom.: 0 Cov.: 23 AF XY: 0.0000302 AC XY: 1AN XY: 33097
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GnomAD3 exomes AF: 0.000115 AC: 21AN: 182769Hom.: 0 AF XY: 0.000134 AC XY: 9AN XY: 67283
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GnomAD4 exome AF: 0.0000401 AC: 44AN: 1097653Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 15AN XY: 363109
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GnomAD4 genome AF: 0.0000451 AC: 5AN: 110913Hom.: 0 Cov.: 23 AF XY: 0.0000302 AC XY: 1AN XY: 33097
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary factor VIII deficiency disease Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1995 | - - |
Thrombophilia, X-linked, due to factor 8 defect Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Benign
T;.
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at