rs7058826
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1
The NM_000132.4(F8):c.1010-27G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,204,928 control chromosomes in the GnomAD database, including 9,109 homozygotes. There are 54,452 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.13 ( 798 hom., 4072 hem., cov: 22)
Exomes 𝑓: 0.14 ( 8311 hom. 50380 hem. )
Consequence
F8
NM_000132.4 intron
NM_000132.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.372
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 Benign. Variant got -12 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.87).
BA1
?
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F8 | NM_000132.4 | c.1010-27G>A | intron_variant | ENST00000360256.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F8 | ENST00000360256.9 | c.1010-27G>A | intron_variant | 1 | NM_000132.4 | P1 | |||
F8 | ENST00000647125.1 | c.*886-27G>A | intron_variant, NMD_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.133 AC: 14755AN: 111001Hom.: 795 Cov.: 22 AF XY: 0.122 AC XY: 4064AN XY: 33227
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GnomAD3 exomes AF: 0.123 AC: 22205AN: 180431Hom.: 1143 AF XY: 0.114 AC XY: 7474AN XY: 65571
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GnomAD4 exome AF: 0.145 AC: 158283AN: 1093869Hom.: 8311 Cov.: 30 AF XY: 0.140 AC XY: 50380AN XY: 360243
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GnomAD4 genome ? AF: 0.133 AC: 14768AN: 111059Hom.: 798 Cov.: 22 AF XY: 0.122 AC XY: 4072AN XY: 33295
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ClinVar
Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary factor VIII deficiency disease Benign:2
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 21, 2020 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 19, 2021 | - - |
Computational scores
Source:
Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
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