rs75829132

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000478.6(ALPL):c.863-12C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,608,524 control chromosomes in the GnomAD database, including 22,663 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3243 hom., cov: 31)

Exomes 𝑓: 0.14 ( 19420 hom. )

Consequence

ALPL
NM_000478.6 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0001207

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.362

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 1-21573653-C-G is Benign according to our data. Variant chr1-21573653-C-G is described in ClinVar as [Benign]. Clinvar id is 256234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21573653-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.433 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.863-12C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8 linkuse as main transcript	c.863-12C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000478.6	P1	P05186-1

Frequencies

GnomAD3 genomes

AF:

0.188

AC:

28577

AN:

151668

Hom.:

3231

Cov.:

show subpopulations

Gnomad AFR

AF:

0.262

Gnomad AMI

AF:

0.118

Gnomad AMR

AF:

0.228

Gnomad ASJ

AF:

0.141

Gnomad EAS

AF:

0.446

Gnomad SAS

AF:

0.232

Gnomad FIN

AF:

0.191

Gnomad MID

AF:

0.118

Gnomad NFE

AF:

0.116

Gnomad OTH

AF:

0.184

GnomAD3 exomes

AF:

0.181

AC:

44850

AN:

247172

Hom.:

5126

AF XY:

0.176

AC XY:

23564

AN XY:

133690

show subpopulations

Gnomad AFR exome

AF:

0.260

Gnomad AMR exome

AF:

0.248

Gnomad ASJ exome

AF:

0.134

Gnomad EAS exome

AF:

0.433

Gnomad SAS exome

AF:

0.211

Gnomad FIN exome

AF:

0.182

Gnomad NFE exome

AF:

0.108

Gnomad OTH exome

AF:

0.155

GnomAD4 exome

AF:

0.144

AC:

209887

AN:

1456740

Hom.:

19420

Cov.:

AF XY:

0.145

AC XY:

104989

AN XY:

724640

show subpopulations

Gnomad4 AFR exome

AF:

0.276

Gnomad4 AMR exome

AF:

0.245

Gnomad4 ASJ exome

AF:

0.138

Gnomad4 EAS exome

AF:

0.508

Gnomad4 SAS exome

AF:

0.216

Gnomad4 FIN exome

AF:

0.179

Gnomad4 NFE exome

AF:

0.115

Gnomad4 OTH exome

AF:

0.158

GnomAD4 genome

AF:

0.189

AC:

28627

AN:

151784

Hom.:

3243

Cov.:

AF XY:

0.196

AC XY:

14525

AN XY:

74156

show subpopulations

Gnomad4 AFR

AF:

0.262

Gnomad4 AMR

AF:

0.228

Gnomad4 ASJ

AF:

0.141

Gnomad4 EAS

AF:

0.448

Gnomad4 SAS

AF:

0.232

Gnomad4 FIN

AF:

0.191

Gnomad4 NFE

AF:

0.116

Gnomad4 OTH

AF:

0.188

Alfa

AF:

0.0929

Hom.:

176

Bravo

AF:

0.197

Asia WGS

AF:

0.327

AC:

1135

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

- -

Hypophosphatasia

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

Cadd

Benign

0.75

Dann

Benign

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.072

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