rs121918010

Positions:

chr1-21573781-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5PP3_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 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:14O:1

Conservation

PhyloP100: 7.58

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

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 [Likely_pathogenic]. Clinvar id is 13673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21573781-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALPL	NM_000478.6 linkuse as main transcript	c.979T>C	p.Phe327Leu	missense_variant	9/12	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8 linkuse as main transcript	c.979T>C	p.Phe327Leu	missense_variant	9/12	1	NM_000478.6	ENSP00000363973	P1	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

GnomAD3 exomes

AF:

0.0000717

AC:

AN:

251200

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135822

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00179

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.223

Hom.:

2350

Bravo

AF:

0.0000302

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypophosphatasia

Pathogenic:4Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 09, 2018	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 30, 2017	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	JKU Lab, Dept of Paediatrics, Johannes Kepler University	Jun 11, 2024	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

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 28, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2022	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) -

Infantile hypophosphatasia

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1996	- -

Adult hypophosphatasia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	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). -

ALPL-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2023

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. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 06, 2022

- -

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

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

MutationTaster

Benign

1.0

A;A;A;A;A;A

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over