rs34605986

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000478.6(ALPL):c.1565T>C(p.Val522Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,597,356 control chromosomes in the GnomAD database, including 9,914 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V522I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.080 ( 594 hom., cov: 33)

Exomes 𝑓: 0.11 ( 9320 hom. )

Consequence

ALPL
NM_000478.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: -0.497

Publications

26 publications found

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 Gene-Disease associations (from GenCC):

adult hypophosphatasia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
childhood hypophosphatasia
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, ClinGen, Orphanet
hypophosphatasia
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, G2P
infantile hypophosphatasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia
odontohypophosphatasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
perinatal lethal hypophosphatasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ALPL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 220 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 1.2672 (below the threshold of 3.09). Trascript score misZ: 1.9021 (below the threshold of 3.09). GenCC associations: The gene is linked to adult hypophosphatasia, infantile hypophosphatasia, odontohypophosphatasia, childhood hypophosphatasia, hypophosphatasia, perinatal lethal hypophosphatasia.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013977885).

BP6

Variant 1-21577638-T-C is Benign according to our data. Variant chr1-21577638-T-C is described in ClinVar as Benign. ClinVar VariationId is 193996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6 link	c.1565T>C	p.Val522Ala	missense_variant	Exon 12 of 12	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8 link	c.1565T>C	p.Val522Ala	missense_variant	Exon 12 of 12	1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes

AF:

0.0805

AC:

12243

AN:

152130

Hom.:

590

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0366

Gnomad AMI

AF:

0.146

Gnomad AMR

AF:

0.0759

Gnomad ASJ

AF:

0.100

Gnomad EAS

AF:

0.00328

Gnomad SAS

AF:

0.152

Gnomad FIN

AF:

0.0602

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.110

Gnomad OTH

AF:

0.0817

GnomAD2 exomes

AF:

0.0961

AC:

21977

AN:

228758

AF XY:

0.102

show subpopulations

Gnomad AFR exome

AF:

0.0339

Gnomad AMR exome

AF:

0.0736

Gnomad ASJ exome

AF:

0.102

Gnomad EAS exome

AF:

0.00223

Gnomad FIN exome

AF:

0.0559

Gnomad NFE exome

AF:

0.111

Gnomad OTH exome

AF:

0.0944

GnomAD4 exome

AF:

0.109

AC:

158043

AN:

1445108

Hom.:

9320

Cov.:

AF XY:

0.111

AC XY:

79829

AN XY:

719296

show subpopulations

African (AFR)

AF:

0.0333

AC:

1111

AN:

33406

American (AMR)

AF:

0.0735

AC:

3273

AN:

44504

Ashkenazi Jewish (ASJ)

AF:

0.0957

AC:

2493

AN:

26042

East Asian (EAS)

AF:

0.00162

AC:

AN:

39574

South Asian (SAS)

AF:

0.164

AC:

14125

AN:

85868

European-Finnish (FIN)

AF:

0.0599

AC:

2345

AN:

39158

Middle Eastern (MID)

AF:

0.0782

AC:

450

AN:

5752

European-Non Finnish (NFE)

AF:

0.115

AC:

128068

AN:

1110632

Other (OTH)

AF:

0.102

AC:

6114

AN:

60172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

9167

18334

27502

36669

45836

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4588

9176

13764

18352

22940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0804

AC:

12247

AN:

152248

Hom.:

594

Cov.:

AF XY:

0.0784

AC XY:

5834

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0365

AC:

1518

AN:

41546

American (AMR)

AF:

0.0757

AC:

1159

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.100

AC:

348

AN:

3470

East Asian (EAS)

AF:

0.00329

AC:

AN:

5174

South Asian (SAS)

AF:

0.152

AC:

736

AN:

4830

European-Finnish (FIN)

AF:

0.0602

AC:

639

AN:

10606

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.110

AC:

7494

AN:

67992

Other (OTH)

AF:

0.0833

AC:

176

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

598

1195

1793

2390

2988

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

154

308

462

616

770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0931

Hom.:

255

Bravo

AF:

0.0781

TwinsUK

AF:

0.114

AC:

423

ALSPAC

AF:

0.112

AC:

432

ESP6500AA

AF:

0.0357

AC:

155

ESP6500EA

AF:

0.0967

AC:

822

ExAC

AF:

0.0936

AC:

11262

Asia WGS

AF:

0.0830

AC:

293

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 24, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Aug 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypophosphatasia

Benign:3Other:1

Dec 10, 2024

JKU Lab, Dept of Paediatrics, Johannes Kepler University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation;in vitro

This missense variant is present in GnomAD 4.1 (ƒ = 0.109) and affects a weakly conserved amino acid. The variant is predicted to affect protein function (REVEL score: 0.257). Splice-prediction algorithms predict no effect on splicing. In vitro functional studies showed normal ALP activity. This variant has been reported in the literature in individuals affected with ALPL-related conditions (PMID: 30680361). The results of the functional testing and the applied ACMG criteria can be viewed at: https://alplmutationdatabase.jku.at/table/ -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Infantile hypophosphatasia

Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Adult hypophosphatasia

Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Childhood hypophosphatasia

Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.27

CADD

Benign

7.8

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.19

T;.;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.31

.;T;T;T

MetaRNN

Benign

0.0014

T;T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.0

N;.;.;N

PhyloP100

-0.50

PrimateAI

Benign

0.38

PROVEAN

Benign

0.050

N;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.051

T;T;T;T

Sift4G

Uncertain

0.046

D;D;D;D

Polyphen

0.0030

B;.;.;B

Vest4

0.057

MPC

0.49

ClinPred

0.0029

GERP RS

-5.6

Varity_R

0.038

gMVP

0.71

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over