1-21568242-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_000478.6(ALPL):c.787T>C(p.Tyr263His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,613,726 control chromosomes in the GnomAD database, including 21,866 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Y263Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.18 ( 3121 hom., cov: 31)

Exomes 𝑓: 0.14 ( 18745 hom. )

Consequence

ALPL
NM_000478.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16O:1

Conservation

PhyloP100: 0.0570

Publications

48 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 -17 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000478.6

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=0.0024879575).

BP6

Variant 1-21568242-T-C is Benign according to our data. Variant chr1-21568242-T-C is described in ClinVar as Benign. ClinVar VariationId is 198423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6 link	c.787T>C	p.Tyr263His	missense_variant	Exon 7 of 12	ENST00000374840.8	NP_000469.3	P05186-1A0A024RAB4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ALPL	ENST00000374840.8 link	c.787T>C	p.Tyr263His	missense_variant	Exon 7 of 12	1	NM_000478.6	ENSP00000363973.3	P05186-1
ALPL	ENST00000374832.5 link	c.787T>C	p.Tyr263His	missense_variant	Exon 7 of 12	2		ENSP00000363965.1	P05186-1
ALPL	ENST00000540617.5 link	c.622T>C	p.Tyr208His	missense_variant	Exon 6 of 11	2		ENSP00000442672.1	P05186-3
ALPL	ENST00000539907.5 link	c.556T>C	p.Tyr186His	missense_variant	Exon 5 of 10	2		ENSP00000437674.1	P05186-2

Frequencies

GnomAD3 genomes

AF:

0.183

AC:

27756

AN:

151812

Hom.:

3108

Cov.:

show subpopulations

Gnomad AFR

AF:

0.251

Gnomad AMI

AF:

0.118

Gnomad AMR

AF:

0.224

Gnomad ASJ

AF:

0.141

Gnomad EAS

AF:

0.451

Gnomad SAS

AF:

0.233

Gnomad FIN

AF:

0.188

Gnomad MID

AF:

0.118

Gnomad NFE

AF:

0.111

Gnomad OTH

AF:

0.177

GnomAD2 exomes

AF:

0.183

AC:

46072

AN:

251140

AF XY:

0.178

show subpopulations

Gnomad AFR exome

AF:

0.256

Gnomad AMR exome

AF:

0.251

Gnomad ASJ exome

AF:

0.137

Gnomad EAS exome

AF:

0.445

Gnomad FIN exome

AF:

0.183

Gnomad NFE exome

AF:

0.107

Gnomad OTH exome

AF:

0.157

GnomAD4 exome

AF:

0.140

AC:

205273

AN:

1461796

Hom.:

18745

Cov.:

AF XY:

0.141

AC XY:

102884

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.265

AC:

8867

AN:

33478

American (AMR)

AF:

0.246

AC:

10997

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.139

AC:

3627

AN:

26136

East Asian (EAS)

AF:

0.511

AC:

20277

AN:

39698

South Asian (SAS)

AF:

0.217

AC:

18714

AN:

86250

European-Finnish (FIN)

AF:

0.175

AC:

9365

AN:

53396

Middle Eastern (MID)

AF:

0.131

AC:

753

AN:

5762

European-Non Finnish (NFE)

AF:

0.111

AC:

123329

AN:

1111972

Other (OTH)

AF:

0.155

AC:

9344

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

9961

19922

29883

39844

49805

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4978

9956

14934

19912

24890

<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:

0.183

AC:

27806

AN:

151930

Hom.:

3121

Cov.:

AF XY:

0.191

AC XY:

14155

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.252

AC:

10420

AN:

41428

American (AMR)

AF:

0.224

AC:

3420

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.141

AC:

487

AN:

3466

East Asian (EAS)

AF:

0.453

AC:

2325

AN:

5132

South Asian (SAS)

AF:

0.233

AC:

1120

AN:

4812

European-Finnish (FIN)

AF:

0.188

AC:

1981

AN:

10540

Middle Eastern (MID)

AF:

0.116

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.111

AC:

7529

AN:

67970

Other (OTH)

AF:

0.181

AC:

383

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1108

2216

3324

4432

5540

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

290

580

870

1160

1450

<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:

0.142

Hom.:

4822

Bravo

AF:

0.190

TwinsUK

AF:

0.105

AC:

388

ALSPAC

AF:

0.113

AC:

434

ESP6500AA

AF:

0.252

AC:

1109

ESP6500EA

AF:

0.111

AC:

956

ExAC

AF:

0.179

AC:

21693

Asia WGS

AF:

0.327

AC:

1135

AN:

3478

EpiCase

AF:

0.108

EpiControl

AF:

0.110

ClinVar

Significance: Benign

Submissions summary: Benign:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 14, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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 20, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32160374, 31600233, 19931660, 28881669, 9781036, 15824850, 18724009) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypophosphatasia

Benign:3Other:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 06, 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. -

Feb 27, 2025

JKU Lab, Dept of Paediatrics, Johannes Kepler University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant is present in GnomAD 4.1 (f = 0.1444) and affects a highly conserved amino acid in the calcium site domain. The variant is not predicted to affect protein function (REVEL score: 0.187). Splice-prediction algorithms predict no effect on splicing. In vitro functional studies could not detect differences in enzyme activity. This variant has been reported in the literature in individuals affected with ALPL-related conditions. The results of the functional testing and the applied ACMG criteria can be viewed at: https://alplmutationdatabase.jku.at/table/ -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Osteogenesis imperfecta

Benign:1

Jul 09, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.079

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.32

CADD

Benign

9.8

(source)

DANN

Benign

0.69

DEOGEN2

Uncertain

0.56

D;.;.;D

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.071

.;T;T;T

MetaRNN

Benign

0.0025

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.070

N;.;.;N

PhyloP100

0.057

PrimateAI

Benign

0.39

PROVEAN

Benign

1.6

N;N;N;N

REVEL

Benign

0.19

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.59

T;T;T;T

Polyphen

0.0

B;.;.;B

Vest4

0.037

MPC

0.53

ClinPred

0.00041

GERP RS

1.9

Varity_R

0.031

gMVP

0.72

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