19-11576780-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001611.5(ACP5):c.325G>A(p.Gly109Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,613,910 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_001611.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACP5 | NM_001611.5 | c.325G>A | p.Gly109Arg | missense_variant | Exon 3 of 5 | ENST00000648477.1 | NP_001602.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152032Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251488Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135920
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461878Hom.: 0 Cov.: 33 AF XY: 0.0000248 AC XY: 18AN XY: 727242
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152032Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74234
ClinVar
Submissions by phenotype
Spondyloenchondrodysplasia with immune dysregulation Pathogenic:5
Variant summary: ACP5 c.325G>A (p.Gly109Arg) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type domain (IPR004843) 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 3.2e-05 in 251488 control chromosomes. c.325G>A has been reported in multiple individuals affected with Spondyloenchondrodysplasia with immune dysregulation (e.g. Lausch_2011, Gernez_2023, Labcorp (formerly Invitae)). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21217752, 38347954). ClinVar contains an entry for this variant (Variation ID: 29833). Based on the evidence outlined above, the variant was classified as pathogenic. -
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ACMG classification criteria: PS4 strong, PM2 supporting, PM3 very strong, PP3 supporting -
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 109 of the ACP5 protein (p.Gly109Arg). This variant is present in population databases (rs781050795, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of spondyloenchondrodysplasia with immune dysregulation (PMID: 21217752, 26951490; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 29833). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ACP5 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000029833). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 21217752). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Inborn genetic diseases Pathogenic:1
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ACP5-related disorder Pathogenic:1
The ACP5 c.325G>A variant is predicted to result in the amino acid substitution p.Gly109Arg. This variant has been reported along with another variant in ACP5 or in the homozygous state in individuals with spondyloenchondrodysplasia (SPENCD) (Lausch et al. 2011. PubMed ID: 21217752; Briggs et al. 2016. PubMed ID: 26951490). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11687595-C-T) and is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/29833/). This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at