rs121918010

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 25 ACMG points: 25P and 0B. PS1_Very_StrongPM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000478.6(ALPL):c.979T>C(p.Phe327Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,613,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F327G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

ALPL
NM_000478.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 7.58

Publications

33 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: Pathogenic. The variant received 25 ACMG points.

PS1

Transcript NM_000478.6 (ALPL) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000478.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-21573781-TT-GG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2202720.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 1-21573781-T-C is Pathogenic according to our data. Variant chr1-21573781-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6 link	c.979T>C	p.Phe327Leu	missense_variant	Exon 9 of 12	ENST00000374840.8	NP_000469.3	P05186-1A0A024RAB4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8 link	c.979T>C	p.Phe327Leu	missense_variant	Exon 9 of 12	1	NM_000478.6	ENSP00000363973.3		P05186-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000717

AC:

AN:

251200

AF XY:

0.0000515

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000979

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000499

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00179

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111938

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000460

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00135

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.554

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0214

Hom.:

2350

Bravo

AF:

0.0000302

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypophosphatasia

Pathogenic:4Other:1

Mar 30, 2017

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The ALPL c.979T>C (p.Phe327Leu) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 7/120210 control chromosomes at a frequency of 0.0000582, which does not exceed the estimated maximal expected allele frequency of a pathogenic ALPL variant (0.0035355). This variant has been identified as one of the most frequent mutations in patients with mild type hypophosphatasia in Japan. Functional study showed that this variant resulted in decreased enzyme activity and mineralization in cultured cells. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Aug 09, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ALPL c.979T>C (p.Phe327Leu) missense variant is also described in the literature as p.Phe310Leu. Across a selection of the available literature, the p.Phe327Leu variant has been identified in a compound heterozygous state in at least 12 individuals with hypophosphatasia (Ozono et al. 1996; Takinami et al. 2004; Taketani et al. 2014). The p.Phe327Leu variant was also identified in a heterozygous state in two parents of affected probands who were found to have low ALP levels, but mild to absent clinical features (Ozono et al. 1996; Takinami et al. 2004). The p.Phe327Leu variant was absent from at least 40 control individuals and is reported at a frequency of 0.00111 in the East Asian population of the Genome Aggregation Database. Expression of the p.Phe327Leu variant in COS-7 cells resulted in ALP activity that was approximately 65% of wild type (Ozono et al. 1996; Takinami et al. 2004). The p.Phe327Leu variant was also significantly more heat labile than wild type (Takinami et al. 2004). Based on the collective evidence, the p.Phe327Leu variant is classified as pathogenic for hypophosphatasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 11, 2024

JKU Lab, Dept of Paediatrics, Johannes Kepler University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is present in GnomAD with a reported frequency of 0.001738 (v4.1) in the East Asian population. The ACMG criteria applied can be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at -

not provided

Pathogenic:4

Jul 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 327 of the ALPL protein (p.Phe327Leu). This variant is present in population databases (rs121918010, gnomAD 0.1%). This missense change has been observed in individuals with autosomal recessive hypophosphatasia (PMID: 8954059, 9814472, 12412800, 15660230). This variant is also known as p.Phe310Leu. ClinVar contains an entry for this variant (Variation ID: 13673). 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, 9814472, 15137467, 17916236, 18455459). For these reasons, this variant has been classified as Pathogenic. -

Nov 30, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 28, 2016

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Multiple functional studies show the variant results in approximately 70% activity levels compared to wild type, while an additional study suggests the activity may be similar to wild type. The data suggest the variant may contribute to a less severe phenotype; however, this has not been fully established (Ozono K et al., 1996; Cai G et al., 1998; Takinami H et al., 2004; Del Angel G et al., 2020); This variant is associated with the following publications: (PMID: 31857675, 9814472, 8954059, 15137467, 9452105, 24276437, 31014398, 31707452, 31600233, 20301329, 31760938, 32160374, 33452237, 11810413) -

Childhood hypophosphatasia;C0268412:Infantile hypophosphatasia;C0268413:Adult hypophosphatasia

Pathogenic:2

Jun 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM3_VeryStrong+PP4+PS3_Moderate -

Infantile hypophosphatasia

Pathogenic:2

Dec 09, 2019

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_000478.4(ALPL):c.979T>C(F327L, aka F310L) is classified as likely pathogenic in the context of hypophosphatasia. Sources cited for classification include the following: PMID 24276437, 15137467, 15660230, 9452105 and 18455459. Classification of NM_000478.4(ALPL):c.979T>C(F327L, aka F310L) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Dec 01, 1996

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Adult hypophosphatasia

Pathogenic:2

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Likely Pathogenic, for Hypophosphatasia, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3 => Well-established functional studies show a deleterious effect (PMID:18455459). -

Mar 26, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ALPL-related disorder

Pathogenic:1

Nov 22, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ALPL c.979T>C variant is predicted to result in the amino acid substitution p.Phe327Leu. In the compound heterozygous state, this variant has been documented to be pathogenic for mild or severe types of hypophosphatasia (Taketani et al. 2014. PubMed ID: 24276437; Ozono et al. 1996. PubMed ID: 8954059, reported as p.Phe310Leu; Michigami et al. 2019. PubMed ID: 31707452; Mao et al. 2019. PubMed ID: 31760938). Alternate nucleotide changes affecting the same amino acid (p.Phe327Cys, p.Phe327Gly) have been reported to be pathogenic (Mornet et al. 2001. PubMed ID: 11395499, reported as p.Phe310Cys; Taillandier et al. 2001. PubMed ID: 11438998, reported as p.Phe310Gly). This variant is reported in 0.11% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.;.;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

.;D;D;D

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

H;.;.;H

PhyloP100

7.6

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.6

D;D;D;D

REVEL

Pathogenic

0.99

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

D;.;.;D

Vest4

0.98

MutPred

0.98

Loss of methylation at K325 (P = 0.0856);.;.;Loss of methylation at K325 (P = 0.0856);

MVP

0.99

MPC

1.3

ClinPred

0.89

GERP RS

4.5

Varity_R

0.95

gMVP

0.92

Mutation Taster

=0/100

disease causing (ClinVar)

(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