rs121918003
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_ModeratePM1PM5PP3_StrongPP5_Very_Strong
The NM_000478.6(ALPL):c.212G>A(p.Arg71His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,650 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 Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R71C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000478.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALPL | NM_000478.6 | c.212G>A | p.Arg71His | missense_variant | 4/12 | ENST00000374840.8 | NP_000469.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALPL | ENST00000374840.8 | c.212G>A | p.Arg71His | missense_variant | 4/12 | 1 | NM_000478.6 | ENSP00000363973.3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 247944Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134428
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1460494Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4AN XY: 726406
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74320
ClinVar
Submissions by phenotype
Adult hypophosphatasia Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 30, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 23, 2023 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 02, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 71 of the ALPL protein (p.Arg71His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with less severe presentations of hypophosphatasia and autosomal recessive infantile or childhood-onset hypophosphatasia (PMID: 11438998, 19500388, 22322541, 22397652, 25731960, 31760938). This variant is also known as p.Arg54His. ClinVar contains an entry for this variant (Variation ID: 1070177). 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%. Experimental studies have shown that this missense change affects ALPL function (PMID: 19500388). This variant disrupts the p.Arg71 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been observed in individuals with ALPL-related conditions (PMID: 1409720, 10839996, 11760847, 28127875), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 25, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22322541, 11438998, 32160374, 22397652, 19500388, 32973344, 25731960, 12674323) - |
Infantile hypophosphatasia Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital | Feb 01, 2024 | - - |
Hypophosphatasia Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 18, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at