rs121918014

Positions:

chr1-21576582-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_000478.6(ALPL):c.1250A>G(p.Asn417Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,808 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 (★★). Synonymous variant affecting the same amino acid position (i.e. N417N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

ALPL
NM_000478.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 8.60

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 14 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, 6 uncertain in NM_000478.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.954

PP5

Variant 1-21576582-A-G is Pathogenic according to our data. Variant chr1-21576582-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21576582-A-G is described in Lovd as [Likely_pathogenic]. Variant chr1-21576582-A-G 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.1250A>G	p.Asn417Ser	missense_variant	11/12	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.1250A>G	p.Asn417Ser	missense_variant	11/12	1	NM_000478.6	ENSP00000363973.3		P05186-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000199

AC:

AN:

251442

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461764

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Other: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	Eurofins Ntd Llc (ga)	Jul 16, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2024	Published functional studies demonstrate that N417S exhibits a dominant effect on the ALPL protein (PMID: 19500388); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 34633109, 21956185, 29405932, 23688511, 11745997, 19500388, 27998428, 19232125, 28401263, 28939177, 29236161, 28000043, 29160013, 32160374, 28436937, 33069919, 25731960, 37993691, 36444396, 34258332, 33549410, 35878747, 34662886, 37422472) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 20, 2023	The ALPL c.1250A>G; p.Asn417Ser variant (rs121918014) is reported in the literature in numerous heterozygous individuals affected with hypophosphatasia (Durrough 2021, Fauvert 2009, Hepp 2021, Taillandier 2018), and in one compound heterozygous case affected with perinatal hypophosphatasia (Sergi 2001). This variant is also reported in ClinVar (Variation ID: 13679), and is found in the non-Finnish European population with an allele frequency of 0.006% (8/129126 alleles) in the Genome Aggregation Database. In vitro functional analyses demonstrate reduced ALP enzymatic activity and exhibits a dominant negative effect on wild-type enzymatic activity (Del Angel 2020, Fauvert 2009, Sultana 2013). Computational analyses also predict that this variant is deleterious (REVEL: 0.81). Based on available information, this variant is considered to be pathogenic. References: Del Angel G et al. Large-scale in vitro functional testing and novel variant scoring via protein modeling provide insights into alkaline phosphatase activity in hypophosphatasia. Hum Mutat. 2020 Jul;41(7):1250-1262. PMID: 32160374. Durrough C et al. Characterization of physical, functional, and cognitive performance in 15 adults with hypophosphatasia. Bone. 2021 Jan;142:115695. PMID: 33069919. Fauvert D et al. Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles. BMC Med Genet. 2009 Jun 6;10:51. PMID: 19500388. Hepp N et al. Biochemical, clinical and genetic characteristics in adults with persistent hypophosphatasaemia; Data from an endocrinological outpatient clinic in Denmark. Bone Rep. 2021 Jun 28;15:101101. PMID: 34258332. Sergi C et al. Perinatal hypophosphatasia: radiology, pathology and molecular biology studies in a family harboring a splicing mutation (648+1A) and a novel missense mutation (N400S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. Am J Med Genet. 2001 Oct 15;103(3):235-40. PMID: 11745997. Sultana S et al. An asparagine at position 417 of tissue-nonspecific alkaline phosphatase is essential for its structure and function as revealed by analysis of the N417S mutation associated with severe hypophosphatasia. Mol Genet Metab. 2013 Jul;109(3):282-8. PMID: 23688511. Taillandier A et al. Genetic analysis of adults heterozygous for ALPL mutations. J Bone Miner Metab. 2018 Nov;36(6):723-733. PMID: 29236161. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 417 of the ALPL protein (p.Asn417Ser). This variant is present in population databases (rs121918014, gnomAD 0.006%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 11745997, 25731960, 27998428). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Asn400Ser. ClinVar contains an entry for this variant (Variation ID: 13679). 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: 19500388, 23688511). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 23, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 17, 2018	- -

Adult hypophosphatasia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 25, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 30, 2020	- -

Hypophosphatasia

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 05, 2019	Variant summary: ALPL c.1250A>G (p.Asn417Ser) results in a conservative amino acid change located in the Crown domain (Simon-Bouy_2008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251442 control chromosomes (gnomAD). c.1250A>G has been reported in the literature as a single heterozygous variant (i.e. no other variants detected) in multiple individuals with features of mild HPP (odontohypophosphatasia, adult and childhood hypophosphatasia) but also in at least 2 parents that were carriers of the variant without any reported symptoms (Fauvert_2009, Reibel_2009, Whyte_2015). It has also been reported in compound heterozygous state with other pathogenic variants in patients affected with severe perinatal or severe childhood hypophosphatasia (Sergi_2001, Whyte_2015). These data indicate that the variant is very likely to be associated with disease. Using a cell system Fauvert et al reported that this variant has a dominant negative effect (Fauvert_2009) on wild-type enzymatic activity. In addition, Sultana et al performed several functional experiments using an in vitro system and concluded that a complete loss of ALP enzymatic activity resulting from the disruption of its functional dimer structure may represent the molecular basis of HPP associated with ALPL N417S (Sultana_2013). Three ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 11, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. Functional studies have shown this variant to have a dominant negative effect (PMID: 19500388). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Severe forms of hypophosphatasia (perinatal and infantile) are generally associated with autosomal recessive disease, while the milder forms of hypophosphatasia (childhood, adult and odonto) have been associated with both autosomal dominant and recessive disease (PMID: 19500388, 23688511). (N) 0112 - Variants in this gene are known to have reduced penetrance. Reduced penetrance and variable expressivity have been reported in patients (PMID: 31760938). (N) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine (exon 11). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 (8 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (Crown domain; PMID: 18925618, 23688511). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 – Very strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in heterozygous patients with adult hypophosphatasia or odontohypophosphatasia (PMID: 19500388, 28401263, 28436937) and in compound heterozygous state in association with perinatal lethal hypophosphatasia (ClinVar, PMID: 11745997, 18925618). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies showed this variant impairs protein assembly and function (PMID: 23688511). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
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. -

ALPL-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 2024

The ALPL c.1250A>G variant is predicted to result in the amino acid substitution p.Asn417Ser. This variant has been reported in multiple patients with autosomal dominant or recessive hypophosphatasia, and also in patients with odontohypophosphatasia (Sergi et al. 2001. PubMed ID: 11745997; Fauvert et al. 2009. PubMed ID: 19500388; Sultana et al. 2013. PubMed ID: 23688511; Taillandier et al. 2017. PubMed ID: 29236161). Additionally, this variant was shown to confer ~5% enzyme activity compared to wild-type (Del Angel et al 2020. PubMed ID: 32160374). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Infantile hypophosphatasia

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Counsyl

Oct 03, 2018

- -

Childhood hypophosphatasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

The p.Asn417Ser variant detected in this individual is predicted to substitute the asparagine at amino acid position 417 with a serine in the crown domain of the protein. The majority of in silico tools predict this variant is damaging, and functional studies have demonstrated that the p.Asn417Ser variant exerts a dominant negative effect on TNSALP, resulting in lack of dimer formation and reduced activity (PMID: 19500388, PMID: 236885113, PMID: 32160374). This variant is present in large population studies at low frequencies (50 of 1,613,808 alleles, no homozygotes, gnomAD v4.0.0). -

Perinatal lethal hypophosphatasia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 15, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;.;.;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

.;D;D;D

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;.;.;M

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.7

D;D;D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.018

D;D;D;D

Sift4G

Uncertain

0.020

D;D;D;D

Polyphen

1.0

D;.;.;D

Vest4

0.93

MVP

0.98

MPC

1.1

ClinPred

0.92

GERP RS

5.1

Varity_R

0.64

gMVP

0.92

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