rs121909152
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000288.4(PEX7):c.649G>A(p.Gly217Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,613,458 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 Likely pathogenic (★★).
Frequency
Consequence
NM_000288.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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PEX7 | NM_000288.4 | c.649G>A | p.Gly217Arg | missense_variant | Exon 7 of 10 | ENST00000318471.5 | NP_000279.1 | |
PEX7 | NM_001410945.1 | c.535G>A | p.Gly179Arg | missense_variant | Exon 7 of 10 | NP_001397874.1 | ||
PEX7 | XM_006715502.3 | c.355G>A | p.Gly119Arg | missense_variant | Exon 4 of 7 | XP_006715565.1 | ||
PEX7 | XM_047418874.1 | c.526+23724G>A | intron_variant | Intron 5 of 5 | XP_047274830.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251402Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135870
GnomAD4 exome AF: 0.0000808 AC: 118AN: 1461298Hom.: 0 Cov.: 30 AF XY: 0.0000702 AC XY: 51AN XY: 726974
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74336
ClinVar
Submissions by phenotype
Rhizomelic chondrodysplasia punctata type 1 Pathogenic:6Other:1
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NM_000288.3(PEX7):c.649G>A(G217R) is classified as likely pathogenic in the context of type 1 rhizomelic chondrodysplasia punctata. Sources cited for classification include the following: PMID 11781871, 12325024, and 11756410. Classification of NM_000288.3(PEX7):c.649G>A(G217R) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Variant summary: PEX7 c.649G>A (p.Gly217Arg) results in a non-conservative amino acid change located in the WD40-repeat-containing domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 277138 control chromosomes (gnomAD). c.649G>A has been reported in the literature in multiple individuals affected with Rhizomelic Chondrodysplasia Punctata Type 1 (Braverman_1997, Motley_2002). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Motley_2002). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
c.649G>A, p.Gly217Arg variant has previously been reported in trans with a known pathogenic variant, p.Leu292ter in five affected individuals (Braverman N et al., 1997) as well as in the homozygous state in one affected individual (Braverman et al. 2002). It has been shown to induce an import defect where the protein remains mainly cytosolic instead of targeting to the peroxisome (Braverman et al. 2002). In 138 affected individuals, this variant has been observed in 10 alleles (~4%) (Braverman et al. 2002; Motley AM et al., 2002); in the ExAC database, only 2 alleles with this variant has been reported (0.002%). This indicates that the prevalence of this variant is significantly higher in cases compared with controls (Odds ratio 2282; 95% CI 498 – 10466). Multiple in silico algorithms predict a deleterious effect (GERP =4.98; CADD = 19.87; PolyPhen = 1; SIFT = 0). Therefore, this collective evidence supports the classification of the c.649G>A (p.Gly217Arg) as a Pathogenic variant for rhizomelic chondrodysplasia punctata type I. We have confirmed this finding in our laboratory using Sanger sequencing. -
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Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with rhizomelic chondrodysplasia punctata, type 1 (MIM#215100). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v4: 127 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated WD repeat domain, G-beta (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with rhizomelic chondrodysplasia punctata, type 1 (PMID: 12325024) and reported as pathogenic by clinical laboratories in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided Pathogenic:3
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12054588, 20145307, 11781871, 15287046, 10083738, 9472033, 20301447, 9090381, 24172221, 12325024, 11756410, 23572185) -
PS3, PS4, PM2, PP3 -
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Peroxisome biogenesis disorder 9B Pathogenic:3
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This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 217 of the PEX7 protein (p.Gly217Arg). This variant is present in population databases (rs121909152, gnomAD 0.01%). This missense change has been observed in individuals with rhizomelic chondrodysplasia punctata (PMID: 9090381, 11781871, 12325024, 23572185). ClinVar contains an entry for this variant (Variation ID: 7782). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects PEX7 function (PMID: 9472033, 11756410, 12325024). For these reasons, this variant has been classified as Pathogenic. -
Rhizomelic chondrodysplasia punctata type 1;C2749346:Peroxisome biogenesis disorder 9B Pathogenic:1
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Inborn genetic diseases Pathogenic:1
The c.649G>A (p.G217R) alteration is located in exon 7 (coding exon 7) of the PEX7 gene. This alteration results from a G to A substitution at nucleotide position 649, causing the glycine (G) at amino acid position 217 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of 0.004% (11/282,804) total alleles studied. The highest observed frequency was 0.01% (3/24,972) of African alleles. This alteration has been reported compound heterozygous with a second alteration in PEX7 in multiple patients with rhizomelic chondrodysplasia punctata (RCDP) (Braverman, 1997; Braverman, 2002). Motley et al. (2002) also reported this alteration in patients with RCDP. This amino acid position is highly conserved in available vertebrate species. Functional studies showed that this alteration resulted in abnormal cellular localization and defective protein binding in Chinese hamster ovary ZPG207 mutant cells and fibroblasts from patients with RCDP (Braverman, 2002; Mukai, 2002). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Rhizomelic chondrodysplasia punctata Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at