rs121918002

Positions:

chr1-21573683-A-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000478.6(ALPL):c.881A>C(p.Asp294Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,613,606 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D294G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

ALPL
NM_000478.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 8.84

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:

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000478.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-21573683-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2800155.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 1-21573683-A-C is Pathogenic according to our data. Variant chr1-21573683-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 13664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21573683-A-C is described in Lovd as [Pathogenic]. Variant chr1-21573683-A-C 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.881A>C	p.Asp294Ala	missense_variant	9/12	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.881A>C	p.Asp294Ala	missense_variant	9/12	1	NM_000478.6	ENSP00000363973.3		P05186-1

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000359

AC:

AN:

250982

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135696

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000120

AC:

176

AN:

1461702

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000152

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000658

AC:

AN:

151904

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74166

show subpopulations

Gnomad4 AFR

AF:

0.0000726

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000518

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 11, 2024	PP3, PM3_very_strong, PS3_moderate, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	The ALPL c.881A>C; p.Asp294Ala variant, also known as Asp277Ala in legacy nomenclature, is reported in the compound heterozygous state in several individuals with hypophosphatasia (Henthorn 1992, Sperelakis-Beedham 2021, Warren 2021). The variant is listed as pathogenic by several sources in the ClinVar database (Variation ID: 13664) and is reported in the general population with an overall allele frequency of 0.004% (12/282,262 alleles) in the Genome Aggregation Database. The amino acid at codon 294 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.946). In support of this prediction, functional studies show the variant protein has reduced alkaline phosphatase activity (Del Angel 2020, Fukushi-Irie 2000), folds improperly, and forms protein aggregates in the cell (Fukushi-Irie 2000). Based on available information, this variant is classified as pathogenic. References: Fukushi-Irie M et al. Possible interference between tissue-non-specific alkaline phosphatase with an Arg54-->Cys substitution and acounterpart with an Asp277-->Ala substitution found in a compound heterozygote associated with severe hypophosphatasia. Biochem J. 2000 Jun 15;348 Pt 3(Pt 3):633-42. PMID: 10839996. Henthorn PS et al. Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9924-8. PMID: 1409720. Sperelakis-Beedham B et al. Utility of genetic testing for prenatal presentations of hypophosphatasia. Mol Genet Metab. 2021 Mar;132(3):198-203. PMID: 33549410. Warren AM et al Bilateral atypical femoral fractures during denosumab therapy in a patient with adult-onset hypophosphatasia. Endocrinol Diabetes Metab Case Rep. 2021 Sep 1;2021:21-0096. PMID: 34515659. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2024	Retrospective study of twenty individuals heterozygous for p.(D294A) demonstrated that the majority of subjects (18/20) had at least one or more HPP-associated findings such as low alkaline phosphatase activity or clinical history associated with HPP; however, none had a prior clinical diagnosis of HPP (PMID: 32803091); Published in vitro functional studies of this variant (reported as D277A based on alternate nomenclature) indicate reduced alkaline phosphatase activity of the protein due to impaired protein folding and incorrect oligomerization (PMID: 10839996); 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: 36444396, 34633109, 34627339, 39667031, 23509830, 19335222, 1409720, 30719581, 29659871, 11547844, 31707452, 18937943, 15694177, 25731960, 22397652, 32160374, 34000433, 32973344, 34125233, 33549410, 34515659, 34662886, 10839996, 38884565, 37993691, 32803091) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 30, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 294 of the ALPL protein (p.Asp294Ala). This variant is present in population databases (rs121918002, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive hypophosphatasia (PMID: 1409720, 15694177, 19335222, 22397652, 25731960). This variant is also known as p.Asp277Ala. ClinVar contains an entry for this variant (Variation ID: 13664). 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: 10839996). For these reasons, this variant has been classified as Pathogenic. -

Hypophosphatasia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 19, 2016	Variant summary: The ALPL c.881A>C (p.Asp294Ala) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 2/119828 control chromosomes at a frequency of 0.0000167, which does not exceed the estimated maximal expected allele frequency of a pathogenic ALPL variant (0.0035355). The variant was found in multiple affected individuals with established dx hypophosphatasia with significantly reduced enzymatic activity. In addition, one reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 11, 2021	- -

Adult hypophosphatasia

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 15, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -

Childhood hypophosphatasia

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 15, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	-	The p.Asp294Ala variant results in the substitution of a highly conserved aspartic acid with alanine at amino acid position 294 of the ALPL protein (also referred to as p.Asp277Ala in some literature). This variant is present in large population databases (186 of 1,613,606 alleles, no homozygotes gnomADv4.1.0). Functional studies have shown that this variant has reduced activity (PMID: 10839996, PMID: 32160374). It does not have a significant dominant-negative effect (Del Angel et al., 2020). The p.Asp294Ala variant has been reported in multiple individuals affected with hypophosphatasia, the majority of whom were found to carry a second variant pathogenic ALPL variant, consistent with autosomal recessive inheritance (PMID: 1409720, PMID: 15694177, PMID: 22397652, PMID: 25731960). In some individuals with hypophosphatasia who are heterozygous for this variant, a second ALPL variant was not identified (PMID: 25731960, PMID: 36444396). One study of individuals heterozygous for this variant found that while the majority had related findings (low alkaline phosphatase, bone disease), none carried a clinical diagnosis of hypophosphatasia (PMID: 32803091). -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 06, 2022

- -

Osteogenesis imperfecta

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

ALPL-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2022

The ALPL c.881A>C variant is predicted to result in the amino acid substitution p.Asp294Ala. This variant is also referred as p.Asp277Ala. This variant has been reported in compound heterozygous state in multiple individuals with hypophosphatasia (reported as p.Asp277Ala in Table 1, Henthorn et al. 1992. PubMed ID: 1409720; Whyte et al. 2012. PubMed ID: 22397652; Brun-Heath et al. 2004. PubMed ID: 15694177; https://alplmutationdatabase.jku.at/table/). Functional studies show that this variant confers significantly reduced enzyme activity (Fukushi-Irié et al. 2000. PubMed ID: 10839996; Del Angel et al. 2020. PubMed ID: 32160374). This variant is interpreted as pathogenic. -

Infantile hypophosphatasia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 15, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.95

D;.;.;D

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

.;D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.8

L;.;.;L

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-6.7

D;D;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.011

D;D;D;D

Sift4G

Benign

0.085

T;T;T;T

Polyphen

1.0

D;.;.;D

Vest4

0.96

MVP

0.98

MPC

1.4

ClinPred

0.71

GERP RS

3.9

Varity_R

0.80

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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