NM_000478.6:c.472+12delG

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000478.6(ALPL):c.472+12delG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,607,190 control chromosomes in the GnomAD database, including 20,642 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1634 hom., cov: 29)

Exomes 𝑓: 0.15 ( 19008 hom. )

Consequence

ALPL
NM_000478.6 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.351

Publications

2 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 -16 ACMG points.

BP6

Variant 1-21563291-CG-C is Benign according to our data. Variant chr1-21563291-CG-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 295543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6 link	c.472+12delG		intron_variant	Intron 5 of 11	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8 link	c.472+8delG		splice_region_variant, intron_variant	Intron 5 of 11	1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes

AF:

0.139

AC:

21079

AN:

152012

Hom.:

1634

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0971

Gnomad AMI

AF:

0.189

Gnomad AMR

AF:

0.125

Gnomad ASJ

AF:

0.178

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0606

Gnomad FIN

AF:

0.141

Gnomad MID

AF:

0.191

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.138

GnomAD2 exomes

AF:

0.128

AC:

31336

AN:

245186

AF XY:

0.130

show subpopulations

Gnomad AFR exome

AF:

0.0945

Gnomad AMR exome

AF:

0.0870

Gnomad ASJ exome

AF:

0.176

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.148

Gnomad NFE exome

AF:

0.175

Gnomad OTH exome

AF:

0.152

GnomAD4 exome

AF:

0.154

AC:

224548

AN:

1455060

Hom.:

19008

Cov.:

AF XY:

0.153

AC XY:

110669

AN XY:

722962

show subpopulations

African (AFR)

AF:

0.0936

AC:

3127

AN:

33408

American (AMR)

AF:

0.0927

AC:

4127

AN:

44514

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

4631

AN:

25740

East Asian (EAS)

AF:

0.000354

AC:

AN:

39584

South Asian (SAS)

AF:

0.0623

AC:

5336

AN:

85678

European-Finnish (FIN)

AF:

0.149

AC:

7871

AN:

52790

Middle Eastern (MID)

AF:

0.206

AC:

1152

AN:

5588

European-Non Finnish (NFE)

AF:

0.171

AC:

189675

AN:

1107662

Other (OTH)

AF:

0.143

AC:

8615

AN:

60096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

10533

21065

31598

42130

52663

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6416

12832

19248

25664

32080

<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:

0.139

AC:

21081

AN:

152130

Hom.:

1634

Cov.:

AF XY:

0.135

AC XY:

10046

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0971

AC:

4030

AN:

41516

American (AMR)

AF:

0.125

AC:

1907

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.178

AC:

616

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.0609

AC:

293

AN:

4812

European-Finnish (FIN)

AF:

0.141

AC:

1491

AN:

10592

Middle Eastern (MID)

AF:

0.188

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.180

AC:

12229

AN:

67970

Other (OTH)

AF:

0.136

AC:

287

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

912

1824

2735

3647

4559

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

230

460

690

920

1150

<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:

0.164

Hom.:

412

Bravo

AF:

0.134

Asia WGS

AF:

0.0340

AC:

118

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Nov 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 24, 2017

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The ALPL c.472+12delG variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 15185/113438 control chromosomes (1198 homozygotes) at a frequency of 0.1338617, which is approximately 38 times the estimated maximal expected allele frequency of a pathogenic ALPL variant (0.0035355), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as likely benign. Taken together, this variant is classified as benign.

Feb 11, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hypophosphatasia

Benign:4

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 24, 2025

JKU Lab, Dept of Paediatrics, Johannes Kepler University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This intronic variant is present in GnomAD 4.1 (15.3% (20642 homozygotes)). REVEL score is not applicable. Splice-prediction algorithms predict no effect on splicing. This variant has been reported in the literature in individuals affected with ALPL-related conditions (PMID 34935951, 34097127, 12357339 and 27777120). The applied ACMG criteria can be viewed at: https://alplmutationdatabase.jku.at/table/

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Aug 29, 2025

Genomenon, Inc, Genomenon, Inc

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

ALPL c.472+12del is an intronic variant located in intron 5. This variant is present at high allele frequency in population databases. In conclusion, we classify ALPL c.472+12del as a benign variant.

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.35

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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