rs121918019

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18O:1

Conservation

PhyloP100: 9.55

Variant links:

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]

ALPL links:

ALPL (HGNC:):

ALPL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 3 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	Protein	UniProt
ALPL	NM_000478.6 linkuse as main transcript	c.526G>A	p.Ala176Thr	missense_variant	6/12	ENST00000374840.8	NP_000469.3	P05186-1A0A024RAB4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8 linkuse as main transcript	c.526G>A	p.Ala176Thr	missense_variant	6/12	1	NM_000478.6	ENSP00000363973.3		P05186-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

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:

AN:

251038

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135748

show subpopulations

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.:

Cov.:

AF XY:

0.000216

AC XY:

157

AN XY:

727182

show subpopulations

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:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74450

show subpopulations

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.:

Bravo

AF:

0.0000982

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

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	Revvity Omics, Revvity	Dec 30, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2024	Published functional studies demonstrate A176T reduces ALP activity (PMID: 19500388, 10679946); 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 (PMID: 18559907); 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, 19500388, 20089612, 10679946, 11855933, 11438998, 29160033, 28580391, 29774402, 27030892, 29160013, 15660230, 29236161, 29354166, 34515659, 35197081, 36007526, 34662886, 34258332, 30576866, 33299629, 25731960, 34426522, 31589614, 32160374, 33549410, 34633109, 31707452, 30283912, 36361766, 36514157, 32811521, 18559907, 36444396, 19232125, 34213743) -
Likely pathogenic, no assertion criteria provided	clinical testing	Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	Jul 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ALPL: PM1, PM2, PM5, PS4:Moderate, PP4, PS3:Supporting -

Hypophosphatasia

Pathogenic:3Other:1

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. -
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	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative or loss of function are known mechanisms of disease in this gene and are associated with infantile, childhood, and adult hypophosphatasia (MIM# 241500, 241510, 146300 respectively) and odontohypophosphatasia (MIM#146300). Later-onset/mild disease is associated with dominant negative variants or loss of function variants that retain residual enzyme activity, while early-onset/severe disease is caused by more complete loss of function variants (PMID: 19500388, 20301329). (I) 0108 - This gene is associated with both recessive and dominant disease. Later-onset/mild disease has been reported with both autosomal dominant and recessive inheritance, while early-onset/severe disease is typically inherited in an autosomal recessive pattern (PMID: 19500388, 20301329). (I) 0112 - The condition associated with this gene has incomplete penetrance. Depending on the pathogenic variant, heterozygous carriers may be asymptomatic or have mild disease (PMID: 20301329). (I) 0115 - Variants in this gene are known to have variable expressivity. Variants associated with autosomal dominant disease may cause variable clinical symptoms in affected family members (PMID: 20301329). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (27 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated alkaline phosphatase domain (Pfam). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in many individuals in a heterozygous or compound heterozygous state, with disease ranging from infantile to adult onset hypophosphatasia (ClinVar, PMID: 19500388, 32811521, 31707452, 25731960). Disease severity is thought to be correlated with the second co-inherited pathogenic variant; individuals reported as heterozygous may have had an unidentified second pathogenic variant (PMID: 19500388). Unaffected carriers of this variant have also been reported (PMID: 18559907). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro functional assays show this variant results in approximately 30% residual enzyme activity, and does not act in a dominant negative manner (PMID: 19500388). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

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	- -

Adult hypophosphatasia

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2024	- -

Childhood hypophosphatasia

Pathogenic:2

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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2008	- -

Osteogenesis imperfecta

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 30, 2021

- -

ALPL-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

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. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.;.;D

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D;D;D

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;.;.;M

PrimateAI

Uncertain

0.74

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over