rs34605986

Positions:

chr1-21577638-T-C

Variant summary

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

The NM_000478.6(ALPL):c.1565T>C(p.Val522Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,597,356 control chromosomes in the GnomAD database, including 9,914 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V522I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.080 ( 594 hom., cov: 33)

Exomes 𝑓: 0.11 ( 9320 hom. )

Consequence

ALPL
NM_000478.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: -0.497

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 (MetaRNN=0.0013977885).

BP6

Variant 1-21577638-T-C is Benign according to our data. Variant chr1-21577638-T-C is described in ClinVar as [Benign]. Clinvar id is 193996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21577638-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.143 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.1565T>C	p.Val522Ala	missense_variant	12/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8 linkuse as main transcript	c.1565T>C	p.Val522Ala	missense_variant	12/12	1	NM_000478.6	P1	P05186-1

Frequencies

GnomAD3 genomes

AF:

0.0805

AC:

12243

AN:

152130

Hom.:

590

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0366

Gnomad AMI

AF:

0.146

Gnomad AMR

AF:

0.0759

Gnomad ASJ

AF:

0.100

Gnomad EAS

AF:

0.00328

Gnomad SAS

AF:

0.152

Gnomad FIN

AF:

0.0602

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.110

Gnomad OTH

AF:

0.0817

GnomAD3 exomes

AF:

0.0961

AC:

21977

AN:

228758

Hom.:

1252

AF XY:

0.102

AC XY:

12871

AN XY:

126330

show subpopulations

Gnomad AFR exome

AF:

0.0339

Gnomad AMR exome

AF:

0.0736

Gnomad ASJ exome

AF:

0.102

Gnomad EAS exome

AF:

0.00223

Gnomad SAS exome

AF:

0.167

Gnomad FIN exome

AF:

0.0559

Gnomad NFE exome

AF:

0.111

Gnomad OTH exome

AF:

0.0944

GnomAD4 exome

AF:

0.109

AC:

158043

AN:

1445108

Hom.:

9320

Cov.:

AF XY:

0.111

AC XY:

79829

AN XY:

719296

show subpopulations

Gnomad4 AFR exome

AF:

0.0333

Gnomad4 AMR exome

AF:

0.0735

Gnomad4 ASJ exome

AF:

0.0957

Gnomad4 EAS exome

AF:

0.00162

Gnomad4 SAS exome

AF:

0.164

Gnomad4 FIN exome

AF:

0.0599

Gnomad4 NFE exome

AF:

0.115

Gnomad4 OTH exome

AF:

0.102

GnomAD4 genome

AF:

0.0804

AC:

12247

AN:

152248

Hom.:

594

Cov.:

AF XY:

0.0784

AC XY:

5834

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0365

Gnomad4 AMR

AF:

0.0757

Gnomad4 ASJ

AF:

0.100

Gnomad4 EAS

AF:

0.00329

Gnomad4 SAS

AF:

0.152

Gnomad4 FIN

AF:

0.0602

Gnomad4 NFE

AF:

0.110

Gnomad4 OTH

AF:

0.0833

Alfa

AF:

0.0967

Hom.:

246

Bravo

AF:

0.0781

TwinsUK

AF:

0.114

AC:

423

ALSPAC

AF:

0.112

AC:

432

ESP6500AA

AF:

0.0357

AC:

155

ESP6500EA

AF:

0.0967

AC:

822

ExAC

AF:

0.0936

AC:

11262

Asia WGS

AF:

0.0830

AC:

293

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 24, 2014	- -
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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hypophosphatasia

Benign:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
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

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.27

CADD

Benign

7.8

DANN

Benign

0.65

DEOGEN2

Benign

0.19

T;.;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.31

.;T;T;T

MetaRNN

Benign

0.0014

T;T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.0

N;.;.;N

MutationTaster

Benign

1.0

P;P;P;P;P;P;P

PrimateAI

Benign

0.38

PROVEAN

Benign

0.050

N;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.051

T;T;T;T

Sift4G

Uncertain

0.046

D;D;D;D

Polyphen

0.0030

B;.;.;B

Vest4

0.057

MPC

0.49

ClinPred

0.0029

GERP RS

-5.6

Varity_R

0.038

gMVP

0.71

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