rs121918016

Positions:

chr1-21577439-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000374840.8(ALPL):c.1366G>A(p.Gly456Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging 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. G456E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ALPL
ENST00000374840.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.54

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 18 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in ENST00000374840.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-21577440-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1511003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 1-21577439-G-A is Pathogenic according to our data. Variant chr1-21577439-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21577439-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.1366G>A	p.Gly456Arg	missense_variant	12/12	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.1366G>A	p.Gly456Arg	missense_variant	12/12	1	NM_000478.6	ENSP00000363973	P1	P05186-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460086

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726460

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Infantile hypophosphatasia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1996

- -

Adult hypophosphatasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Sep 02, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. Late-onset/mild disease is associated with monoallelic dominant negative variants or biallelic loss of function variants that retain residual enzyme activity, while early-onset/severe disease is caused by more complete loss of function variants (PMIDs: 20301329, 19500388). (I) 0108 - This gene is 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). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301329). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301329). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated alkaline phosphatase domain (DECIPHER). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. These alternative changes, p.(Gly456Ala) and p.(Gly456Glu), have been reported as pathogenic or likely pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic (ClinVar), and observed in both a compound heterozygous individual with neonatal hypophosphatasia (PMID: 8954059), and heterozygous individuals with hypophosphatasia or infantile hypophosphatasia (PMID: 31641588, 31267001, 34258332, 19500388). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected COS-7 cells have demonstrated significantly reduced ALP enzyme activity (PMID: 8954059). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 19, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 456 of the ALPL protein (p.Gly456Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hypophosphatasia (PMID: 8954059, 19500388, 31641588). This variant is also known as Gly439Arg. ClinVar contains an entry for this variant (Variation ID: 13681). 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: 8954059, 19500388). For these reasons, this variant has been classified as Pathogenic. -

Hypophosphatasia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

JKU Lab, Dept of Paediatrics, Johannes Kepler University

Aug 22, 2023

Absent in GnomAD. Further information about the ACMG criteria applied can be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at/ -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;.;.;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

H;.;.;H

MutationTaster

Benign

1.0

A;A;A;A;A;A;A

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.5

D;D;D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;.;.;D

Vest4

0.95

MutPred

0.99

Gain of solvent accessibility (P = 0.0584);.;.;Gain of solvent accessibility (P = 0.0584);

MVP

0.98

MPC

1.4

ClinPred

1.0

GERP RS

4.9

Varity_R

0.94

gMVP

0.99

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