rs121918010

chr1-21573781-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1 PM1 PM5 PP3_Strong PP5_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 same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F327C) 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 7.58

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PS1: Transcript NM_000478.6 (ALPL) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2840424
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000478.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-21573782-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1457572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	UniProt
ALPL	NM_000478.6	c.979T>C	p.Phe327Leu	missense_variant	9/12	ENST00000374840.8

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152148 Hom.: 0 Cov.: 32

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: 18 AN: 251200 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135822

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: 73 AN: 1461784 Hom.: 0 Cov.: 32 AF XY: 0.0000523 AC XY: 38 AN XY: 727200

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: 7 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74322

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: 7

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypophosphatasia Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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, 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	-	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 28, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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	- -

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

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). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 28, 2023	- -

Childhood hypophosphatasia;C0268412:Infantile hypophosphatasia;C0268413:Adult hypophosphatasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 06, 2022

- -

ALPL-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;.;.;H
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.63	T
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	D
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

Other links and lift over

dbSNP: rs121918010; hg19: chr1-21900274;