rs33921347
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_000132.4(F8):c.4500G>A(p.Pro1500=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,210,190 control chromosomes in the GnomAD database, including 49 homozygotes. There are 808 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.013 ( 19 hom., 403 hem., cov: 22)
Exomes 𝑓: 0.0014 ( 30 hom. 405 hem. )
Consequence
F8
NM_000132.4 synonymous
NM_000132.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.256
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 -19 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
BP6
Variant X-154929290-C-T is Benign according to our data. Variant chrX-154929290-C-T is described in ClinVar as [Benign]. Clinvar id is 255223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154929290-C-T is described in Lovd as [Likely_pathogenic].
BP7
Synonymous conserved (PhyloP=0.256 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0128 (1436/112085) while in subpopulation AFR AF= 0.0449 (1385/30833). AF 95% confidence interval is 0.043. There are 19 homozygotes in gnomad4. There are 403 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 19 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F8 | NM_000132.4 | c.4500G>A | p.Pro1500= | synonymous_variant | 14/26 | ENST00000360256.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F8 | ENST00000360256.9 | c.4500G>A | p.Pro1500= | synonymous_variant | 14/26 | 1 | NM_000132.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0128 AC: 1435AN: 112033Hom.: 19 Cov.: 22 AF XY: 0.0118 AC XY: 403AN XY: 34223
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GnomAD3 exomes AF: 0.00371 AC: 679AN: 182837Hom.: 12 AF XY: 0.00234 AC XY: 158AN XY: 67477
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GnomAD4 exome AF: 0.00140 AC: 1537AN: 1098105Hom.: 30 Cov.: 33 AF XY: 0.00111 AC XY: 405AN XY: 363467
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GnomAD4 genome AF: 0.0128 AC: 1436AN: 112085Hom.: 19 Cov.: 22 AF XY: 0.0118 AC XY: 403AN XY: 34285
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ClinVar
Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 31, 2023 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Hereditary factor VIII deficiency disease Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at