chr1-21561126-C-A
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000478.6(ALPL):c.211C>A(p.Arg71Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,638 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in 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 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALPL | NM_000478.6 | c.211C>A | p.Arg71Ser | missense_variant | Exon 4 of 12 | ENST00000374840.8 | NP_000469.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460638Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726480
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Adult hypophosphatasia Pathogenic:1
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not provided Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 71 of the ALPL protein (p.Arg71Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with childhood-type hypophosphatasia (PMID: 11760847). ClinVar contains an entry for this variant (Variation ID: 2676552). 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 ALPL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ALPL function (PMID: 11760847). This variant disrupts the p.Arg71 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11438998, 19500388, 22397652, 25731960, 31760938). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at