1-21573678-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000478.6(ALPL):c.876A>G(p.Pro292=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,612,332 control chromosomes in the GnomAD database, including 22,830 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. PGD292P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.19 ( 3281 hom., cov: 31)

Exomes 𝑓: 0.14 ( 19549 hom. )

Consequence

ALPL
NM_000478.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -6.95

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 1-21573678-A-G is Benign according to our data. Variant chr1-21573678-A-G is described in ClinVar as [Benign]. Clinvar id is 256238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21573678-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-6.95 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6 linkuse as main transcript	c.876A>G	p.Pro292=	synonymous_variant	9/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8 linkuse as main transcript	c.876A>G	p.Pro292=	synonymous_variant	9/12	1	NM_000478.6	P1	P05186-1

Frequencies

GnomAD3 genomes

AF:

0.189

AC:

28657

AN:

151840

Hom.:

3269

Cov.:

show subpopulations

Gnomad AFR

AF:

0.263

Gnomad AMI

AF:

0.118

Gnomad AMR

AF:

0.227

Gnomad ASJ

AF:

0.141

Gnomad EAS

AF:

0.449

Gnomad SAS

AF:

0.232

Gnomad FIN

AF:

0.191

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.116

Gnomad OTH

AF:

0.185

GnomAD3 exomes

AF:

0.184

AC:

46024

AN:

249588

Hom.:

5373

AF XY:

0.179

AC XY:

24167

AN XY:

134932

show subpopulations

Gnomad AFR exome

AF:

0.266

Gnomad AMR exome

AF:

0.251

Gnomad ASJ exome

AF:

0.137

Gnomad EAS exome

AF:

0.436

Gnomad SAS exome

AF:

0.213

Gnomad FIN exome

AF:

0.185

Gnomad NFE exome

AF:

0.110

Gnomad OTH exome

AF:

0.158

GnomAD4 exome

AF:

0.145

AC:

211698

AN:

1460372

Hom.:

19549

Cov.:

AF XY:

0.146

AC XY:

105880

AN XY:

726498

show subpopulations

Gnomad4 AFR exome

AF:

0.277

Gnomad4 AMR exome

AF:

0.247

Gnomad4 ASJ exome

AF:

0.139

Gnomad4 EAS exome

AF:

0.508

Gnomad4 SAS exome

AF:

0.216

Gnomad4 FIN exome

AF:

0.180

Gnomad4 NFE exome

AF:

0.116

Gnomad4 OTH exome

AF:

0.159

GnomAD4 genome

AF:

0.189

AC:

28707

AN:

151960

Hom.:

3281

Cov.:

AF XY:

0.196

AC XY:

14561

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.263

Gnomad4 AMR

AF:

0.228

Gnomad4 ASJ

AF:

0.141

Gnomad4 EAS

AF:

0.450

Gnomad4 SAS

AF:

0.231

Gnomad4 FIN

AF:

0.191

Gnomad4 NFE

AF:

0.116

Gnomad4 OTH

AF:

0.188

Alfa

AF:

0.109

Hom.:

519

Bravo

AF:

0.197

Asia WGS

AF:

0.327

AC:

1136

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 17, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2018	- -

Hypophosphatasia

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

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

BayesDel_noAF

Benign

-0.83

Cadd

Benign

0.028

Dann

Benign

0.45

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