NM_000478.6:c.1309+46C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000478.6(ALPL):c.1309+46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0924 in 1,610,428 control chromosomes in the GnomAD database, including 12,691 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.086 ( 1246 hom., cov: 32)

Exomes 𝑓: 0.093 ( 11445 hom. )

Consequence

ALPL
NM_000478.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.24

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 1-21576687-C-T is Benign according to our data. Variant chr1-21576687-C-T is described in ClinVar as Benign. ClinVar VariationId is 256227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6 link	c.1309+46C>T		intron_variant	Intron 11 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.1309+46C>T		intron_variant	Intron 11 of 11	1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes

AF:

0.0860

AC:

13059

AN:

151896

Hom.:

1235

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0176

Gnomad AMI

AF:

0.0703

Gnomad AMR

AF:

0.184

Gnomad ASJ

AF:

0.109

Gnomad EAS

AF:

0.454

Gnomad SAS

AF:

0.208

Gnomad FIN

AF:

0.105

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0649

Gnomad OTH

AF:

0.0981

GnomAD2 exomes

AF:

0.133

AC:

33227

AN:

249746

AF XY:

0.131

show subpopulations

Gnomad AFR exome

AF:

0.0166

Gnomad AMR exome

AF:

0.223

Gnomad ASJ exome

AF:

0.106

Gnomad EAS exome

AF:

0.447

Gnomad FIN exome

AF:

0.106

Gnomad NFE exome

AF:

0.0639

Gnomad OTH exome

AF:

0.106

GnomAD4 exome

AF:

0.0931

AC:

135730

AN:

1458414

Hom.:

11445

Cov.:

AF XY:

0.0956

AC XY:

69314

AN XY:

725310

show subpopulations

African (AFR)

AF:

0.0123

AC:

412

AN:

33398

American (AMR)

AF:

0.214

AC:

9547

AN:

44576

Ashkenazi Jewish (ASJ)

AF:

0.107

AC:

2778

AN:

26028

East Asian (EAS)

AF:

0.509

AC:

20123

AN:

39554

South Asian (SAS)

AF:

0.193

AC:

16634

AN:

86004

European-Finnish (FIN)

AF:

0.0985

AC:

5229

AN:

53088

Middle Eastern (MID)

AF:

0.0812

AC:

467

AN:

5748

European-Non Finnish (NFE)

AF:

0.0671

AC:

74420

AN:

1109860

Other (OTH)

AF:

0.102

AC:

6120

AN:

60158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

5760

11520

17280

23040

28800

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3198

6396

9594

12792

15990

<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:

0.0861

AC:

13086

AN:

152014

Hom.:

1246

Cov.:

AF XY:

0.0949

AC XY:

7047

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.0175

AC:

726

AN:

41468

American (AMR)

AF:

0.185

AC:

2825

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.109

AC:

379

AN:

3472

East Asian (EAS)

AF:

0.456

AC:

2337

AN:

5126

South Asian (SAS)

AF:

0.208

AC:

997

AN:

4802

European-Finnish (FIN)

AF:

0.105

AC:

1114

AN:

10592

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0648

AC:

4405

AN:

67964

Other (OTH)

AF:

0.104

AC:

220

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

532

1063

1595

2126

2658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

146

292

438

584

730

<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:

0.0754

Hom.:

118

Bravo

AF:

0.0886

Asia WGS

AF:

0.308

AC:

1068

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 20, 2018

GeneDx

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

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

Childhood 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

Hypophosphatasia

Benign:1

Aug 29, 2025

Genomenon, Inc, Genomenon, Inc

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

ALPL c.1309+46C>T is an intronic variant located in intron 11. This variant is present at high allele frequency in population databases. In conclusion, we classify ALPL c.1309+46C>T as a benign variant.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.36

(source)

DANN

Benign

0.57

PhyloP100

-1.2

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