rs121918000

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_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 (★★).

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 12 ACMG points.

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/exons	MANE	Protein	UniProt
ALPL	NM_000478.6 linkuse as main transcript	c.535G>A	p.Ala179Thr	missense_variant	6/12	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8 linkuse as main transcript	c.535G>A	p.Ala179Thr	missense_variant	6/12	1	NM_000478.6	ENSP00000363973	P1	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

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 15, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ALPL function (PMID: 9562633, 12162492, 23509830, 32160374). 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. ClinVar contains an entry for this variant (Variation ID: 13662). This variant is also known as Ala162Thr. This missense change has been observed in individual(s) with clinical features of hypophosphatasia (PMID: 3174660, 11438998, 32160374; Invitae). This variant is present in population databases (rs121918000, gnomAD 0.003%). 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). -

Infantile hypophosphatasia

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 30, 2024	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Aug 01, 2014	- -

Hypophosphatasia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2021	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 25, 2020	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 26, 2022

- -

Adult hypophosphatasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 14, 2024

- -

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

MutationTaster

Benign

1.0

A;A;A;A;A

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