NM_000478.6:c.1363G>A

Variant names:

• chr1-21577436-G-A
• rs149889416
• NM_000478.6:c.1363G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000478.6(ALPL):​c.1363G>A​(p.Gly455Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,612,488 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. G455D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.71
• Publications: 7 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000478.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-21577437-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1464855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.847
• PP5: Variant 1-21577436-G-A is Pathogenic according to our data. Variant chr1-21577436-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 371400.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	c.1363G>A	p.Gly455Ser	missense_variant	Exon 12 of 12	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8	c.1363G>A	p.Gly455Ser	missense_variant	Exon 12 of 12	1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000449 AC: 11 AN: 245118 AF XY: 0.0000374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000100

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1460286 Hom.: 0 Cov.: 33 AF XY: 0.0000523 AC XY: 38 AN XY: 726546

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000692 AC: 77 AN: 1111932

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000614 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ALPL p.Gly455Ser variant has been identified in multiple publications in association with hypophosphatasia (HPP). A case study of a stillborn patient with severe skeletal symptoms consistent with perinantal lethal HPP with compound heterozgyous mutations in the ALPL gene including the G455S variant inherited paternally and a R428P variant interited maternally; ALP enzymatic activity in serum of the father with the G455S variant was 50U/l (reference range: 40-150 U/l), suggesting normal enzyme activity however on the lower end (Olech_2016_PMID: 27179278). Another case study of a patient with progressive renal failure leading to bone pain and multiple fractures revealed that he was compound heterozygous for the G455S variant as well as a T117H ALPL variant. Functional studies of the G455S variant demonstrated normal enzymatic activity compared to wildtype which was then impaired when extracellular phosphate concentrations were increased; this change in phosphate concentration did not affect wildtype activity suggesting a genetic and environmental component to the phenotype (Cundy_2015_PMID: 25736332). A functional study by Brun-Health et al. (2007) showed abnormal cellular localization of the G455S ALPL mutant construct compared to wildtype (Brun-Heath_2007_PMID: 17719863). This variant was identified in 1/105 patients with HPP in the compound heterozygous state; the patient with this variant was determined to have mild childhood HPP (Whyte_2015_PMID: 25731960). The p.G455S variant was identified in dbSNP (ID: rs149889416) and in Clinvar (classified as likely pathogenic by Counsyl for infantile hypophosphatasia). The variant was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 11 of 245118 chromosomes at a frequency of 0.000045 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following population: European (non-Finnish) in 11 of 109950 chromosomes (freq: 0.0001); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Gly455 residue is conserved in mammals but not more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

Jan 30, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies of residual alkaline phosphatase activity compared to wildtype yield inconsistent results (Brun-Heath et al., 2007; Fauvert et al., 2009; Cundy et al., 2015; Del Angel et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17719863, 15135428, 27179278, 25736332, 18328985, 19500388, 25731960, 32160374, 31589614) -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 455 of the ALPL protein (p.Gly455Ser). This variant is present in population databases (rs149889416, gnomAD 0.01%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 15135428, 17719863, 25731960, 25736332, 27179278). This variant is also known as G438S. ClinVar contains an entry for this variant (Variation ID: 371400). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 17719863). For these reasons, this variant has been classified as Pathogenic. -

Hypophosphatasia Pathogenic:2

Sep 07, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of the available literature, the ALPL c.1363G>A (p.Gly455Ser) missense variant has been reported in a compound heterozygous state in at least five individuals diagnosed with hypophosphatasia, including four with a mild form of the disease, and one with a perinatal lethal form (Draguet et al. 2004; Brun-Heath et al. 2007; Fauvert et al. 2009; Olech et al. 2016). The p.Gly455Ser variant was also identified in a heterozygous state in two reportedly unaffected fathers. The father of a severely affected patient had a serum alkaline phosphatase activity within normal limits. Control data are unavailable for this variant, which is reported at a frequency of 0.000102 in the European (non-Finnish) population of the Genome Aggregation Database. Transient expression studies in COS-7 cells revealed that compared to the wildtype protein, the p.Gly455Ser variant protein exhibited reduced expression at the cell membrane and was retained in the cytoplasm and Golgi, suggesting that the variant protein is unable to dimerize and undergo glycosylation (Brun-Heath et al. 2007). Site-directed mutagenesis studies showed that the variant, which is located in the vicinity of the active site, exhibited 71% of wildtype alkaline phosphatase activity (Brun-Heath et al. 2007). This is consistent with the finding that alkaline phosphatase activity in serum from the healthy individual who was heterozygous for the variant, was at the low end of the reference range (Olech et al. 2016). Based on the collective evidence, the p.Gly455Ser variant is classified as pathogenic for hypophosphatasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Mar 19, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ALPL c.1363G>A (p.Gly455Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 245118 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALPL causing Hypophosphatasia (4.5e-05 vs 0.0035), allowing no conclusion about variant significance. c.1363G>A has been reported in the literature in multiple individuals affected with Hypophosphatasia (e.g., Brun-Heath_2007, Cundy_2015, Draguet_2004, Olech_2016, Seefried_2021, Whyte_2015). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 17719863, 25736332, 15135428, 27179278, 32987199, 25731960). ClinVar contains an entry for this variant (Variation ID: 371400). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Apr 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Infantile hypophosphatasia Pathogenic:1

Sep 14, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Adult hypophosphatasia Pathogenic:1

Feb 27, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Childhood hypophosphatasia Pathogenic:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	.;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	1.9	L;.;.;L
PhyloP100		7.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Benign	0.15	T;T;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		1.0	D;.;.;D
Vest4		0.67
MVP		0.96
MPC		1.2
ClinPred		0.58	D
GERP RS		4.0
Varity_R		0.38
gMVP		0.94
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs149889416; hg19: chr1-21903929;