chr1-150081372-C-G
Variant summary
Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_007259.5(VPS45):c.718C>G(p.Leu240Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000212 in 1,607,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L240L) has been classified as Likely benign.
Frequency
Consequence
NM_007259.5 missense
Scores
Clinical Significance
Conservation
Publications
- congenital neutropenia-myelofibrosis-nephromegaly syndromeInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151958Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000123 AC: 3AN: 244458 AF XY: 0.0000151 show subpopulations
GnomAD4 exome AF: 0.0000220 AC: 32AN: 1455268Hom.: 0 Cov.: 31 AF XY: 0.0000152 AC XY: 11AN XY: 724064 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152076Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74322 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Congenital neutropenia-myelofibrosis-nephromegaly syndrome Uncertain:2
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This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 240 of the VPS45 protein (p.Leu240Val). This variant is present in population databases (rs587716374, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with VPS45-related conditions. ClinVar contains an entry for this variant (Variation ID: 474246). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt VPS45 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Inborn genetic diseases Uncertain:1
The c.718C>G (p.L240V) alteration is located in exon 8 (coding exon 8) of the VPS45 gene. This alteration results from a C to G substitution at nucleotide position 718, causing the leucine (L) at amino acid position 240 to be replaced by a valine (V). 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