rs148803046
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS1_Supporting
The NM_005529.7(HSPG2):c.5335C>T(p.Arg1779Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000556 in 1,614,002 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_005529.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000210 AC: 32AN: 152106Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000159 AC: 40AN: 251036Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135698
GnomAD4 exome AF: 0.000592 AC: 865AN: 1461778Hom.: 1 Cov.: 34 AF XY: 0.000556 AC XY: 404AN XY: 727184
GnomAD4 genome AF: 0.000210 AC: 32AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74412
ClinVar
Submissions by phenotype
not provided Uncertain:5
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1779 of the HSPG2 protein (p.Arg1779Trp). This variant is present in population databases (rs148803046, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with HSPG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 197489). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. -
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In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
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Inborn genetic diseases Uncertain:1
The c.5335C>T (p.R1779W) alteration is located in exon 42 (coding exon 42) of the HSPG2 gene. This alteration results from a C to T substitution at nucleotide position 5335, causing the arginine (R) at amino acid position 1779 to be replaced by a tryptophan (W). 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