rs781272386

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000478.6(ALPL):c.815G>A(p.Arg272His) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,918 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. R272C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ALPL
NM_000478.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.84

Publications

6 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 17 ACMG points.

PM1

In a hotspot region, there are 3 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 chr1-21570326-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13684.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, 0.983

PP5

Variant 1-21570327-G-A is Pathogenic according to our data. Variant chr1-21570327-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495882.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.815G>A	p.Arg272His	missense_variant	Exon 8 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.815G>A	p.Arg272His	missense_variant	Exon 8 of 12	1	NM_000478.6	ENSP00000363973.3		P05186-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152088

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251330

AF XY:

0.0000147

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111972

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000197

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

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:

0.000104

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

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

Mar 02, 2020

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect (Brun-Heath et al., 2005); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 32160374, 29236161, 28663156, 19500388, 15694177) -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 272 of the ALPL protein (p.Arg272His). This variant is present in population databases (rs781272386, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of autosomal dominant and recessive ALPL-related conditions (PMID: 15694177, 28663156, 29236161). This variant is also known as R255H. ClinVar contains an entry for this variant (Variation ID: 495882). 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: 15694177). This variant disrupts the p.Arg272 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17253930, 18559907, 24276437, 24378058). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Feb 24, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ALPL c.815G>A; p.Arg272His variant (rs781272386), also known as R255H, is reported in the literature in individuals affected with autosomal dominant and recessive hypophosphatasia (Brun-Heath 2005, Saglam 2017, Taillandier 2018). This variant is also reported in ClinVar (Variation ID: 495882) and is found in the non-Finnish European population with an allele frequency of 0.003% (4/129072 alleles) in the Genome Aggregation Database. Additionally, other variants at this codon (c.814C>T, p.Arg272Cys; c.815G>T, p.Arg272Leu) have been reported in individuals with ALPL- related conditions and are considered pathogenic (Del Angel 2020, Zhang 2021). Functional analyses of the variant protein show reduced enzyme activity (Brun-Heath 2005, Del Angel 2020). Computational analyses predict that this variant is deleterious (REVEL: 0.896). Based on available information, this variant is considered to be pathogenic. References: Brun-Heath I et al. Characterization of 11 novel mutations in the tissue non-specific alkaline phosphatase gene responsible for hypophosphatasia and genotype-phenotype correlations. Mol Genet Metab. 2005 Mar;84(3):273-7. PMID: 15694177. Del Angel G et al. Large-scale in vitro functional testing and novel variant scoring via protein modeling provide insights into alkaline phosphatase activity in hypophosphatasia. Hum Mutat. 2020 Jul;41(7):1250-1262. PMID: 32160374. Saglam H et al. Clinical and Genetic Findings of Turkish Hypophosphatasia Cases. J Clin Res Pediatr Endocrinol. 2017 Sep 1;9(3):229-236. PMID: 28663156. Taillandier A et al. Genetic analysis of adults heterozygous for ALPL mutations. J Bone Miner Metab. 2018 Nov;36(6):723-733. PMID: 29236161. Zhang L et al. Molecular diagnosis for 55 fetuses with skeletal dysplasias by whole-exome sequencing: A retrospective cohort study. Clin Genet. 2021 Aug;100(2):219-226. PMID: 33942288. -

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

Pathogenic:1

Jun 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteogenesis imperfecta

Pathogenic:1

Jun 14, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Infantile hypophosphatasia

Pathogenic:1

May 09, 2018

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

Mar 19, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypophosphatasia

Pathogenic:1

Jul 12, 2017

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The ALPL c.815G>A (p.Arg272His) variant (alternatively also known as R255H) involves the alteration of a conserved nucleotide, resulting in a missense change residing in the alkaline-phosphatase-like core domain (InterPro). 3/3 in silico tools predict damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0000083 (1/120878 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic ALPL variant (0.0035355). The variant has been identified in a homozgous patient with hypophosphatasia (HPP), with in vitro functional studies showing that residual enzyme activity is < 10% of WT levels (Brun-Heath_MGM_2005). In addition, molecular modeling suggests the variant lies within a conserved calcium-binding domain, which is supported by the fact that several variants at the same codon are found in HPP patients (R272C, R272L), suggesting the residue is critical for protein function. The variant has not been classified in reputable databases or by clinical diagnostics laboratories. Taken together, this variant is classified as likely pathogenic until additional HPP patients with the variant are identified. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;.;.;D

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.63

.;T;T;T

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;.;.;M

PhyloP100

3.8

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.7

D;D;D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.013

D;D;D;D

Sift4G

Uncertain

0.012

D;D;D;D

Polyphen

0.99

D;.;.;D

Vest4

0.79

MutPred

0.94

Loss of MoRF binding (P = 0.0633);.;.;Loss of MoRF binding (P = 0.0633);

MVP

0.98

MPC

0.70

ClinPred

0.95

GERP RS

5.2

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.61

gMVP

0.80

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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