rs747488546
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000478.6(ALPL):c.658G>A(p.Gly220Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G220A) has been classified as Pathogenic.
Frequency
Consequence
NM_000478.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALPL | NM_000478.6 | c.658G>A | p.Gly220Arg | missense_variant | 7/12 | ENST00000374840.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALPL | ENST00000374840.8 | c.658G>A | p.Gly220Arg | missense_variant | 7/12 | 1 | NM_000478.6 | P1 | |
ALPL | ENST00000374832.5 | c.658G>A | p.Gly220Arg | missense_variant | 7/12 | 2 | P1 | ||
ALPL | ENST00000540617.5 | c.493G>A | p.Gly165Arg | missense_variant | 6/11 | 2 | |||
ALPL | ENST00000539907.5 | c.427G>A | p.Gly143Arg | missense_variant | 5/10 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251468Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135914
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461832Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727212
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Adult hypophosphatasia Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Mar 02, 2022 | ACMG classification criteria: PS4 supporting, PM2 moderated, PM3 moderated, PM5 moderated, PP3 supporting - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 13, 2024 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 220 of the ALPL protein (p.Gly220Arg). This variant is present in population databases (rs747488546, gnomAD 0.003%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 22397652, 25731960). ClinVar contains an entry for this variant (Variation ID: 554408). 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 expected to disrupt ALPL protein function. This variant disrupts the p.Gly220 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12815606, 22394703, 22397652, 28663156). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Infantile hypophosphatasia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 17, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at