rs781272386

chr1-21570327-G-Achr1-21570327-G-Cchr1-21570327-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_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:7

Conservation

PhyloP100: 3.84

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 16 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, 6 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.

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. Variant chr1-21570327-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6 linkuse as main transcript	c.815G>A	p.Arg272His	missense_variant	8/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8 linkuse as main transcript	c.815G>A	p.Arg272His	missense_variant	8/12	1	NM_000478.6	P1	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

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251330

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135860

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:

0.0000327

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

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000192

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 24, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 21, 2023	For these reasons, this variant has been classified as Pathogenic. 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. 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). 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. Experimental studies have shown that this missense change affects ALPL function (PMID: 15694177). -

Osteogenesis imperfecta

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 14, 2022

- -

Infantile hypophosphatasia

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Counsyl

May 09, 2018

- -

Adult hypophosphatasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 06, 2023

- -

Hypophosphatasia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jul 12, 2017

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

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;.;.;D

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Benign

0.70

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;.;.;M

MutationTaster

Benign

1.0

D;D;D;D;D;D

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

Varity_R

0.61

gMVP

0.80

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

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