rs121918013
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000478.6(ALPL):c.346G>A(p.Ala116Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,461,516 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A116S) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
ALPL
NM_000478.6 missense
NM_000478.6 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 9.96
Genes affected
ALPL (HGNC:438): (alkaline phosphatase, biomineralization associated) This gene encodes a member of the alkaline phosphatase family of proteins. There are at least four distinct but related alkaline phosphatases: intestinal, placental, placental-like, and liver/bone/kidney (tissue non-specific). The first three are located together on chromosome 2, while the tissue non-specific form is located on chromosome 1. The product of this gene is a membrane bound glycosylated enzyme that is not expressed in any particular tissue and is, therefore, referred to as the tissue-nonspecific form of the enzyme. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature enzyme. This enzyme may play a role in bone mineralization. Mutations in this gene have been linked to hypophosphatasia, a disorder that is characterized by hypercalcemia and skeletal defects. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000478.6
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-21563158-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1466600.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 1-21563158-G-A is Pathogenic according to our data. Variant chr1-21563158-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21563158-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ALPL | NM_000478.6 | c.346G>A | p.Ala116Thr | missense_variant | 5/12 | ENST00000374840.8 | NP_000469.3 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461516Hom.: 0 Cov.: 37 AF XY: 0.0000248 AC XY: 18AN XY: 727088
GnomAD4 exome
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37
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GnomAD4 genome
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33
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 02, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 13, 2022 | Indentified in individuals with severe childhood hypophosphatasia and lethal hypophosphatasia, who also had a second variant in the ALPL gene (Whyte et al., 2015; Tailandier et al., 2001); Published functional studies demonstrate that A116T results in decreased alkaline phosphatase activity via a dominant-negative effect (Lia-Baldini et al., 2001; Foster et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12920074, 25716980, 21168482, 19500388, 10679946, 10872988, 26590809, 28663156, 29236161, 32160374, 11438998, 33160095, 33069919, 34164522, 11479741, 25731960, 27535533) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jan 12, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 116 of the ALPL protein (p.Ala116Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypophosphatasias (PMID: 10679946, 10872988, 11438998, 12920074, 25731960). It has also been observed to segregate with disease in related individuals. This variant is also known as A94T and A99T. ClinVar contains an entry for this variant (Variation ID: 13677). 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: 21168482, 25716980). For these reasons, this variant has been classified as Pathogenic. - |
Adult hypophosphatasia Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Feb 06, 2023 | PS3, PS4, PM2, PP3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2003 | - - |
Hypophosphatasia Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 28, 2019 | Variant summary: ALPL c.346G>A (p.Ala116Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251048 control chromosomes (gnomAD). c.346G>A has been reported in the literature in multiple individuals affected with Hypophosphatasia (Hu_2000, Herasse_2003, Whyte_2015). These data indicate that the variant is very likely to be associated with disease. In vitro studies show that this variant leads to severely reduced alkaline phosphatase activity, also showing a weak dominant negative effect when co-expressed with the wild-type enzyme (Lia-Baldini_2001, Fauvert_2009, Ishida_2011) with consistent finding by an in vivo mouse model study (Foster_2011). Four ClinVar submissions (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
ALPL-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 28, 2024 | The ALPL c.346G>A variant is predicted to result in the amino acid substitution p.Ala116Thr. This variant has been documented to be causative for both autosomal dominant and autosomal recessive hypophosphatasia (HPP), and functional studies support its pathogenicity (see examples: Hu et al. 2000. PubMed ID: 10872988; Taillandier et al. 2001. PubMed ID: 11438998; Herasse et al. 2003. PubMed ID: 12920074; Fauvert et al. 2009. PubMed ID: 19500388; Ishida et al. 2011. PubMed ID: 21168482). This variant is also referred to as p.Ala99Thr in the literature. This variant has not been reported in a large population database, indicating this variant is rare. This variant is classified as pathogenic. - |
Infantile hypophosphatasia Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Oct 24, 2014 | - - |
Childhood hypophosphatasia Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2003 | - - |
Odontohypophosphatasia Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2003 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;H
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
D;.;.;D
Vest4
MutPred
Gain of glycosylation at T115 (P = 0.1061);.;.;Gain of glycosylation at T115 (P = 0.1061);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at