rs149344982

Positions:

chr1-21563267-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1PM5BP4_StrongBP6_Very_StrongBS1BS2

The NM_000478.6(ALPL):c.455G>A(p.Arg152His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,612,314 control chromosomes in the GnomAD database, including 226 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R152C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0090 ( 13 hom., cov: 33)

Exomes 𝑓: 0.013 ( 213 hom. )

Consequence

ALPL
NM_000478.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19O:1

Conservation

PhyloP100: 0.283

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 Benign. 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 0 benign, 8 uncertain in NM_000478.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-21563266-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1470828.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=2}.

BP4

Computational evidence support a benign effect (MetaRNN=0.006093651).

BP6

Variant 1-21563267-G-A is Benign according to our data. Variant chr1-21563267-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 197679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21563267-G-A is described in Lovd as [Pathogenic]. Variant chr1-21563267-G-A is described in Lovd as [Benign]. Variant chr1-21563267-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00896 (1361/151928) while in subpopulation SAS AF= 0.032 (154/4808). AF 95% confidence interval is 0.0279. There are 13 homozygotes in gnomad4. There are 677 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALPL	NM_000478.6 link	c.455G>A	p.Arg152His	missense_variant	5/12	ENST00000374840.8	NP_000469.3	P05186-1A0A024RAB4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8 link	c.455G>A	p.Arg152His	missense_variant	5/12	1	NM_000478.6	ENSP00000363973.3		P05186-1

Frequencies

GnomAD3 genomes

AF:

0.00898

AC:

1364

AN:

151810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00261

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00742

Gnomad ASJ

AF:

0.00982

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0326

Gnomad FIN

AF:

0.00680

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0124

Gnomad OTH

AF:

0.0134

GnomAD3 exomes

AF:

0.0115

AC:

2872

AN:

249266

Hom.:

AF XY:

0.0133

AC XY:

1793

AN XY:

134942

show subpopulations

Gnomad AFR exome

AF:

0.00155

Gnomad AMR exome

AF:

0.00629

Gnomad ASJ exome

AF:

0.00752

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0293

Gnomad FIN exome

AF:

0.00788

Gnomad NFE exome

AF:

0.0126

Gnomad OTH exome

AF:

0.0122

GnomAD4 exome

AF:

0.0132

AC:

19300

AN:

1460386

Hom.:

213

Cov.:

AF XY:

0.0138

AC XY:

10023

AN XY:

726352

show subpopulations

Gnomad4 AFR exome

AF:

0.00212

Gnomad4 AMR exome

AF:

0.00676

Gnomad4 ASJ exome

AF:

0.00752

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0302

Gnomad4 FIN exome

AF:

0.00772

Gnomad4 NFE exome

AF:

0.0132

Gnomad4 OTH exome

AF:

0.0151

GnomAD4 genome

AF:

0.00896

AC:

1361

AN:

151928

Hom.:

Cov.:

AF XY:

0.00912

AC XY:

677

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.00260

Gnomad4 AMR

AF:

0.00741

Gnomad4 ASJ

AF:

0.00982

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.0320

Gnomad4 FIN

AF:

0.00680

Gnomad4 NFE

AF:

0.0124

Gnomad4 OTH

AF:

0.0133

Alfa

AF:

0.0108

Hom.:

Bravo

AF:

0.00791

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.0117

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0144

AC:

124

ExAC

AF:

0.0112

AC:

1363

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0165

EpiControl

AF:

0.0170

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2018	This variant is associated with the following publications: (PMID: 32160374, 31793067, 28492530, 27884173, 21228398, 11438998, 22995991, 21956185, 25023282) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	ALPL: PM5, BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, gene and variant associated with hypophosphatasia -

Hypophosphatasia

Benign:2Other:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Osteogenesis imperfecta

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 18, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 07, 2021

- -

Infantile hypophosphatasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Adult hypophosphatasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Childhood hypophosphatasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.61

D;.;.;D

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.68

.;T;T;T

MetaRNN

Benign

0.0061

T;T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

0.81

L;.;.;L

PrimateAI

Benign

0.28

PROVEAN

Benign

1.4

N;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.43

T;T;T;T

Sift4G

Benign

0.23

T;T;T;T

Polyphen

0.072

B;.;.;B

Vest4

0.063

MPC

0.56

ClinPred

0.011

GERP RS

2.6

Varity_R

0.039

gMVP

0.76

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