rs149889416

Positions:

chr1-21577436-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.71

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:

ALPL (HGNC:):

ALPL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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 [Likely_pathogenic]. Clinvar id is 1464855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 [Likely_pathogenic]. Clinvar id is 371400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21577436-G-A 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.1363G>A	p.Gly455Ser	missense_variant	12/12	ENST00000374840.8	NP_000469.3	P05186-1A0A024RAB4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8 linkuse as main transcript	c.1363G>A	p.Gly455Ser	missense_variant	12/12	1	NM_000478.6	ENSP00000363973.3		P05186-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000449

AC:

AN:

245118

Hom.:

AF XY:

0.0000374

AC XY:

AN XY:

133648

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

AN:

1460286

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

726546

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000692

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000771

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	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). 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: 17719863). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2023	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) -
Likely pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 29, 2024

- -

Infantile hypophosphatasia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Sep 14, 2016

- -

Childhood hypophosphatasia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Adult hypophosphatasia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 27, 2024

- -

Hypophosphatasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 07, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;.;.;D

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

.;D;D;D

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.85

D;D;D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Benign

1.9

L;.;.;L

PrimateAI

Uncertain

0.72

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

GERP RS

4.0

Varity_R

0.38

gMVP

0.94

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