rs1229517379
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000478.6(ALPL):c.1460C>T(p.Ala487Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,572 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A487A) has been classified as Likely benign.
Frequency
Consequence
NM_000478.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALPL | NM_000478.6 | c.1460C>T | p.Ala487Val | missense_variant | 12/12 | ENST00000374840.8 | NP_000469.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALPL | ENST00000374840.8 | c.1460C>T | p.Ala487Val | missense_variant | 12/12 | 1 | NM_000478.6 | ENSP00000363973.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1454572Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 724018
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Adult hypophosphatasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
Childhood hypophosphatasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center of Excellence in Genomics and Precision Dentistry, Faculty of Dentistry, Chulalongkorn University | - | The compound heterozygous variants, c.1460C>T (p.Ala487Val) and c.1479C>A (p.Asn493Lys), in ALPL gene were identified in a patient diagnosed with hypochondroplasia (HCH) and hypophosphatasia (HPP). Her mother was heterozygous for the c.1460C>T (p.Ala487Val) while her father was heterozygous for the c.1479C>A (p.Asn493Lys). Both altered amino acid positions are highly conserved among species. She was also identified the with the heterozygous missense variant, c.1612A>G (p.Ile538Val) in FGFR3 (Porntaveetus et al., 2017). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 487 of the ALPL protein (p.Ala487Val). 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: 26432670, 28763161, 31077853). 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: 556895). 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 with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
Infantile hypophosphatasia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 28, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at