12-6019295-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP2BS2_Supporting
The NM_000552.5(VWF):c.4123C>T(p.Pro1375Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,782 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000552.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000151 AC: 38AN: 250938Hom.: 2 AF XY: 0.0000884 AC XY: 12AN XY: 135680
GnomAD4 exome AF: 0.0000301 AC: 44AN: 1461646Hom.: 2 Cov.: 38 AF XY: 0.0000193 AC XY: 14AN XY: 727132
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74306
ClinVar
Submissions by phenotype
not provided Uncertain:2
The VWF c.4123C>T; p.Pro1375Ser variant (rs751767496), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 439336). This variant is found in the Latino/Admixed American population with an allele frequency of 0.1101% (39/35,430 alleles, including 2 homozygotes) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.596). Due to limited information, the clinical significance of this variant is uncertain at this time. -
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not specified Uncertain:1
Variant summary: VWF c.4123C>T (p.Pro1375Ser) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 250938 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in VWF causing Von Willebrand Disease, allowing no conclusion about variant significance. c.4123C>T has been reported in the literature as de novo in an individual affected with Von Willebrand Disease; however, this variant was detected with de novo variants in other genes with unknown disease association (Coban-Akdemir_2020). 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 publication have been ascertained in the context of this evaluation (PMID: 32233023). ClinVar contains an entry for this variant (Variation ID: 439336). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Inborn genetic diseases Uncertain:1
The c.4123C>T (p.P1375S) alteration is located in exon 28 (coding exon 27) of the VWF gene. This alteration results from a C to T substitution at nucleotide position 4123, causing the proline (P) at amino acid position 1375 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at