rs150799088

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM5BP4

The NM_000478.6(ALPL):c.1349G>A(p.Arg450His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,613,154 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R450C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 1 hom. )

Consequence

ALPL
NM_000478.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 0.746

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 Uncertain_significance. Variant got 3 ACMG points.

PM1

In a hotspot region, there are 11 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 chr1-21577421-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 971527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.35421142).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6 linkuse as main transcript	c.1349G>A	p.Arg450His	missense_variant	12/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8 linkuse as main transcript	c.1349G>A	p.Arg450His	missense_variant	12/12	1	NM_000478.6	P1	P05186-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000772

AC:

AN:

246148

Hom.:

AF XY:

0.0000448

AC XY:

AN XY:

134030

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:

0.000426

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000545

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000602

AC:

AN:

1460828

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

726772

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:

0.000383

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000825

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2022	Identified in a patient with reduced alkaline phosphatase activity who also harbored a second variant (phase unknown) in published literature (Taillandier et al., 2000); Published functional studies demonstrate that this variant does not impact enzyme activity levels (Del Angel et al., 2020; Nasu et al., 2006); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17212778, 16769381, 32160374, 23791648, 10679946, 25023282) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 450 of the ALPL protein (p.Arg450His). This variant is present in population databases (rs150799088, gnomAD 0.04%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 10679946). This variant is also known as R433H. ClinVar contains an entry for this variant (Variation ID: 429390). 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. Experimental studies have shown that this missense change does not substantially affect ALPL function (PMID: 17212778, 32160374). This variant disrupts the p.Arg450 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9781036, 17212778, 25731960, 29159075). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 11, 2017	The ALPL: p.Arg450His variant (also reported as R433H; rs150799088) has been previously reported in a patient with odontohypophosphatasia (Taillandier 2000). The patient described in Taillandier et al (2000) also carried a second rare ALPL variant, but further inheritance information, including the phase of the two ALPL variants was not provided. Function studies of the p.Arg450His variant in cell culture could not identify an enzymatic defect (Nasu 2006), although a different variant in the same codon, p.Arg450Cys, lead to a severe disruption in enzyme function (Nasu 2006). However, the p.Arg450Cys variant has been identified as a homozygote in individuals with severe hypophosphatasia (Mornet 1988), and the function defects described in Nasu et al (2006) are likely attributable to the substituted cysteine residue. Furthermore, the p.Arg450His variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in South Asian populations of 0.04% (identified in 13 out of 30,690 chromosomes, including 1 homozygote). Therefore, based on the available information, the clinical significance of the p.Arg450His variant cannot be determined with certainty. -

Infantile hypophosphatasia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 14, 2017	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 29, 2021

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 29, 2022

Variant summary: ALPL c.1349G>A (p.Arg450His) 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 7.7e-05 in 246148 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in ALPL causing Hypophosphatasia (7.7e-05 vs 0.0035), allowing no conclusion about variant significance. c.1349G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Odontoid Hypophosphatasia (example Taillandier_2000 cited in Del Angel_2020). These data do not allow any conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function (example, Nasu_2006 and Del Angel_2020). These results showed no damaging effect of this variant on ALPL activity in-vitro. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hypophosphatasia

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Uncertain

0.043

BayesDel_noAF

Pathogenic

0.15

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;.;.;D

Eigen

Benign

0.068

Eigen_PC

Benign

0.064

FATHMM_MKL

Benign

0.35

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.35

T;T;T;T

MetaSVM

Pathogenic

0.82

MutationAssessor

Benign

2.0

M;.;.;M

MutationTaster

Benign

0.98

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.59

N;N;N;N

REVEL

Uncertain

0.62

Sift

Benign

0.21

T;T;T;T

Sift4G

Benign

0.13

T;T;T;T

Polyphen

0.98

D;.;.;D

Vest4

0.53

MVP

0.95

MPC

1.3

ClinPred

0.14

GERP RS

4.6

Varity_R

0.083

gMVP

0.70

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