rs121918000

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000478.6(ALPL):c.535G>A(p.Ala179Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,742 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. A179V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ALPL
NM_000478.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

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:

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, 5 uncertain in NM_000478.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-21564104-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1520525.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 1-21564103-G-A is Pathogenic according to our data. Variant chr1-21564103-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21564103-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6 link	c.535G>A	p.Ala179Thr	missense_variant	Exon 6 of 12	ENST00000374840.8	NP_000469.3	P05186-1A0A024RAB4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8 link	c.535G>A	p.Ala179Thr	missense_variant	Exon 6 of 12	1	NM_000478.6	ENSP00000363973.3		P05186-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251074

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135762

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461742

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Jan 06, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 179 of the ALPL protein (p.Ala179Thr). This variant is present in population databases (rs121918000, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of hypophosphatasia (PMID: 3174660, 11438998, 32160374; internal data). This variant is also known as Ala162Thr. ClinVar contains an entry for this variant (Variation ID: 13662). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 9562633, 12162492, 23509830, 32160374). For these reasons, this variant has been classified as Pathogenic. -

May 05, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with childhood hypophophatasia who harbored a second ALPL variant of unknown phase in published literature (Whyte et al., 2015; Genest et al., 2018); Reported in a heterozygous adult patient with features of hypophosphatasia in published literature (Schmidt et al., 2019); Published functional studies demonstrate a damaging effect on protein trafficking and enzyme activity (Weiss et al., 1988; Shibata et al., 1998; Di Mauro et al., 2002; Zhu et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also denoted as A162T due to alternative nomenclature; This variant is associated with the following publications: (PMID: 23509830, 9562633, 28991257, 23791648, 31400546, 3174660, 12162492, 11438998, 25731960, 29774402, 31485555, 32368696, 32160374) -

Oct 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Infantile hypophosphatasia

Pathogenic:2

Aug 01, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Oct 30, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hypophosphatasia

Pathogenic:2

Aug 24, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ALPL c.535G>A (p.Ala179Thr) results in a non-conservative amino acid change in 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 1.2e-05 in 251074 control chromosomes (gnomAD). c.535G>A has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Hypophosphatasia (e.g. Weiss_1988, Taillandier_2001, Whyte_2015, Seefried_2017, Del Angel_2020). These data indicate that the variant is very likely to be associated with disease. Experimental evidence obtained from multiple functional studies, demonstrated the variant causes a severe reduction in enzyme activity and affects its stability, transport and mineralisation ability (e.g. Weiss_1988, Fedde_1996, Di Mauro_2002, Zhu_2012, Del Angel_2020). A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 25, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Pathogenic:1

Jan 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Adult hypophosphatasia

Pathogenic:1

Feb 14, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;.;.;D

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

.;D;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

H;.;.;H

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.5

D;D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.025

D;D;D;D

Polyphen

0.85

P;.;.;P

Vest4

0.99

MutPred

0.98

Gain of glycosylation at A179 (P = 0.0474);.;.;Gain of glycosylation at A179 (P = 0.0474);

MVP

0.99

MPC

0.91

ClinPred

0.99

GERP RS

5.3

Varity_R

0.82

gMVP

0.98

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