rs121918019

chr1-21564094-G-Achr1-21564094-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000478.6(ALPL):c.526G>A(p.Ala176Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,614,012 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A176V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 9.55

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000478.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-21564095-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2664865.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 1-21564094-G-A is Pathogenic according to our data. Variant chr1-21564094-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21564094-G-A is described in Lovd as [Pathogenic]. Variant chr1-21564094-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-21564094-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6	c.526G>A	p.Ala176Thr	missense_variant	6/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.526G>A	p.Ala176Thr	missense_variant	6/12	1	NM_000478.6	P1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000916 AC: 23 AN: 251038 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135748

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000222 AC: 325 AN: 1461728 Hom.: 0 Cov.: 32 AF XY: 0.000216 AC XY: 157 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000275

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74450

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000178 Hom.: 0

Bravo AF: 0.0000982

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000741 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 30, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2022	Observed in the compound heterozygous state with the R272C variant in two siblings with HPP; the parent who carried the A176T variant was noted to be tall without physical features of HPP or premature loss of deciduous teeth (Stevenson et al., 2008); Published functional studies demonstrate A176T reduces ALP activity (Fauvert et al., 2009; Taillandier et al., 2000); 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: 16769381, 34258332, 34662886, 19500388, 20089612, 10679946, 11855933, 11438998, 29160033, 28580391, 29774402, 27030892, 29160013, 15660230, 29236161, 29354166, 18559907, 34213743, 34426522, 34515659, 31589614, 33549410, 33299629, 35197081, 32160374) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	ALPL: PM2, PP3, PP4, PS3:Supporting, PS4:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 28, 2020	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Computational tools predict that this variant is damaging. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 176 of the ALPL protein (p.Ala176Thr). This variant is present in population databases (rs121918019, gnomAD 0.02%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 10679946, 11438998, 18559907, 19232125, 25731960). 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: 13683). 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: 10679946, 19500388). For these reasons, this variant has been classified as Pathogenic. -

Hypophosphatasia Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 11-16-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Oct 13, 2020	This variant has been previously reported as single heterozygous variant or in combination with another ALPL alteration in patients with hypophosphatasia (PMID: 32811521, 21713987, 25731960, 10679946, 19500388, 11438998, 29354166, 19232125, 29236161). Experimental studies have shown that this missense change results in reduced enzymatic activity (PMID: 10679946, 19500388, 32160374). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0096% (27/282400) and thus is presumed to be rare. The c.526G>A (p.Ala176Thr) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. An in-frame deletion variant was detected in trans and has been previously reported as a compound heterozygous change in patients with hypophosphatasia (PMID:15660230). Based on the available evidence, the c.526G>A (p.Ala176Thr) variant is classified as Pathogenic. -

Infantile hypophosphatasia Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2008	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 02, 2014	- -

Childhood hypophosphatasia Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Nov 11, 2022	ACMG classification criteria: PS3 supporting, PM2 supporting, PM3 very strong, PP3 supporting, PP4 -

Adult hypophosphatasia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 24, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 30, 2022	- -

Osteogenesis imperfecta Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 30, 2021

- -

Childhood hypophosphatasia;C0268412:Infantile hypophosphatasia;C0268413:Adult hypophosphatasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 10, 2022

- -

ALPL-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2024

The ALPL c.526G>A variant is predicted to result in the amino acid substitution p.Ala176Thr. This variant has been reported as a single heterozygous variant or in combination with another ALPL variant in both children and adults with hypophosphatasia (Reported as p.Ala159Thr, Taillandier et al. 2000. PubMed ID: 10679946; Taillandier et al. 2001. PubMed ID: 11438998; Fauvert et al. 2009. PubMed ID: 19500388; Reibel et al. 2009. PubMed ID: 19232125; Gagnon et al. 2010. PubMed ID: 20089612; Wenkert et al. 2011. PubMed ID: 21713987; Whyte et al. 2015. PubMed ID: 25731960; Vogt et al. 2020. PubMed ID: 32811521). Of note, in some cases mentioned above the c.526G>A (p.Ala176Thr) and other ALPL variant were confirmed to be in the compound heterozygous state, where in others phase was not determined. Functional studies have shown that this variant leads to reduced enzyme activity (Reported as p.Ala159Thr, Taillandier et al. 2000. PubMed ID: 10679946; Fauvert et al. 2009. PubMed ID: 19500388). In addition, this variant is interpreted as pathogenic in the ALPL Mutation Database (https://alplmutationdatabase.jku.at/table/) and as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/13683/). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.;.;M
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.043	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.94
MVP		0.99
MPC		1.2
ClinPred		0.81	D
GERP RS		5.3
Varity_R		0.49
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121918019; hg19: chr1-21890587; COSMIC: COSV100876845;