rs61750096
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP2BP4_StrongBS2_Supporting
The NM_000552.5(VWF):c.4499C>T(p.Ala1500Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1500E) has been classified as Uncertain significance.
Frequency
Consequence
NM_000552.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VWF | NM_000552.5 | c.4499C>T | p.Ala1500Val | missense_variant | 28/52 | ENST00000261405.10 | |
VWF | XM_047429501.1 | c.4499C>T | p.Ala1500Val | missense_variant | 28/52 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VWF | ENST00000261405.10 | c.4499C>T | p.Ala1500Val | missense_variant | 28/52 | 1 | NM_000552.5 | P1 | |
VWF | ENST00000538635.5 | n.421-24985C>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000986 AC: 15AN: 152128Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000259 AC: 65AN: 250966Hom.: 0 AF XY: 0.000265 AC XY: 36AN XY: 135674
GnomAD4 exome AF: 0.0000431 AC: 63AN: 1461670Hom.: 0 Cov.: 99 AF XY: 0.0000371 AC XY: 27AN XY: 727146
GnomAD4 genome ? AF: 0.0000985 AC: 15AN: 152246Hom.: 0 Cov.: 31 AF XY: 0.0000940 AC XY: 7AN XY: 74438
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 13, 2024 | Variant summary: VWF c.4499C>T (p.Ala1500Val) results in a non-conservative amino acid change located in the von Willebrand factor, type A domain (IPR002035) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 250966 control chromosomes. c.4499C>T has been reported in the literature in individuals affected with Von Willebrand Disease without strong evidence for causality (examples: Shen_2016, Veyradier_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Von Willebrand Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27766062, 26986123). ClinVar contains an entry for this variant (Variation ID: 439339). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 03, 2023 | The frequency of this variant in the general population, 0.0035 (70/19938 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with Type 1 and Type 2 VWD (PMIDs: 26986123 (2016) and 27766062 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at