1-21570326-C-T

Position:

chr1-21570326-C-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.814C>T(p.Arg272Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000291 in 1,614,004 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R272H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

ALPL
NM_000478.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 4.75

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 chr1-21570327-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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 1-21570326-C-T is Pathogenic according to our data. 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. Variant chr1-21570326-C-T is described in Lovd as [Pathogenic]. Variant chr1-21570326-C-T 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.814C>T	p.Arg272Cys	missense_variant	8/12	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.814C>T	p.Arg272Cys	missense_variant	8/12	1	NM_000478.6	ENSP00000363973.3		P05186-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152138

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251360

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000387

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74304

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000320

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 16, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 272 of the ALPL protein (p.Arg272Cys). This variant is present in population databases (rs121918020, gnomAD 0.006%). This missense change has been observed in individuals with hypophosphatasia (PMID: 17253930, 18559907, 24276437, 24378058). It has also been observed to segregate with disease in related individuals. This variant is also known as R255C. ClinVar contains an entry for this variant (Variation ID: 13684). 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%. This variant disrupts the p.Arg272 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been observed in individuals with ALPL-related conditions (PMID: 12815606, 15694177, 17253930, 18559907, 24276437, 24378058), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2024	Published functional studies demonstrate a damaging effect on enzymatic activity (PMID: 32160374); 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: 34662886, 24378058, 35320273, 31687651, 32811521, 33942288, 32160374, 17253930, 18559907, 24276437, 33827627) -

Hypophosphatasia

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2021	Variant summary: ALPL c.814C>T (p.Arg272Cys) results in a non-conservative amino acid change located in the calcium site domain (Angel_2020) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251360 control chromosomes. c.814C>T has been reported in the literature as a compound heterozygous genotype in individuals affected with Hypophosphatasia (example, del Angel_2020, Spentchian_2006, Taketani_2014, Zhao_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (del Angel_2020). The most pronounced variant effect results in <10% of normal tissue nonspecific alkaline phosphatase (TNSALP) activity in vitro. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

ALPL-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 08, 2024

The ALPL c.814C>T variant is predicted to result in the amino acid substitution p.Arg272Cys. This variant has been reported in several individuals with autosomal recessive hypophosphatasia (patient 1, Spentchian et al. 2006. PubMed ID: 17253930; Stevenson et al. 2008. PubMed ID: 18559907; Zhao et al. 2013. PubMed ID: 24378058; Zhang et al. 2021. PubMed ID: 33942288; Taketani et al. 2013. PubMed ID: 24276437). In vitro functional studies demonstrate that expression of this variant results in ~6% activity compared to wildtype (Table S1, Del Angel et al. 2020. PubMed ID: 32160374). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. Additionally, different missense changes impacting the same amino acid (p.Arg272His and p.Arg272Leu) have been reported in individuals with hypophosphatasia (Brun-Heath et al. 2004. PubMed ID: 15694177; Spentchian et al. 2003. PubMed ID: 12815606). Taken together, the c.814C>T (p.Arg272Cys) variant is interpreted as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 11, 2024

- -

Infantile hypophosphatasia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2008

- -

Childhood hypophosphatasia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2008

- -

Adult hypophosphatasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.;.;D

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.71

.;T;T;T

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

H;.;.;H

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-6.2

D;D;D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0060

D;D;D;D

Sift4G

Uncertain

0.033

D;D;D;D

Polyphen

1.0

D;.;.;D

Vest4

0.89

MutPred

0.94

Loss of catalytic residue at R272 (P = 0.0412);.;.;Loss of catalytic residue at R272 (P = 0.0412);

MVP

0.99

MPC

1.4

ClinPred

0.99

GERP RS

5.2

Varity_R

0.79

gMVP

0.87

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