rs121918012
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The ENST00000374840.8(ALPL):c.485G>T(p.Gly162Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,632 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. G162S) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000374840.8 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALPL | NM_000478.6 | c.485G>T | p.Gly162Val | missense_variant | 6/12 | ENST00000374840.8 | NP_000469.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALPL | ENST00000374840.8 | c.485G>T | p.Gly162Val | missense_variant | 6/12 | 1 | NM_000478.6 | ENSP00000363973 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461632Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727140
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Childhood hypophosphatasia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1999 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 23, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 162 of the ALPL protein (p.Gly162Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive hypophosphatasia (PMID: 10094560). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Gly145Val. ClinVar contains an entry for this variant (Variation ID: 13676). 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. Experimental studies have shown that this missense change affects ALPL function (PMID: 10332035). For these reasons, this variant has been classified as Pathogenic. - |
Infantile hypophosphatasia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 21, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at