1-21577638-T-C

Variant names:

• chr1-21577638-T-C
• rs34605986
• NM_000478.6:c.1565T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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. 16/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: -0.497
• Publications: 26 publications found

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 Gene-Disease associations (from GenCC):

• adult hypophosphatasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
• childhood hypophosphatasia

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, ClinGen, Orphanet
• hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, G2P
• infantile hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia
• odontohypophosphatasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• perinatal lethal hypophosphatasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 220 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 1.2672 (below the threshold of 3.09). Trascript score misZ: 1.9021 (below the threshold of 3.09). GenCC associations: The gene is linked to adult hypophosphatasia, infantile hypophosphatasia, odontohypophosphatasia, childhood hypophosphatasia, hypophosphatasia, perinatal lethal hypophosphatasia.
• 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 VariationId is 193996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000478.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPL	NM_000478.6	MANE Select	c.1565T>C	p.Val522Ala	missense	Exon 12 of 12	NP_000469.3
	ALPL	NM_001369803.2		c.1565T>C	p.Val522Ala	missense	Exon 12 of 12	NP_001356732.1
	ALPL	NM_001369804.2		c.1565T>C	p.Val522Ala	missense	Exon 12 of 12	NP_001356733.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPL	ENST00000374840.8	TSL:1 MANE Select	c.1565T>C	p.Val522Ala	missense	Exon 12 of 12	ENSP00000363973.3
	ALPL	ENST00000374832.5	TSL:2	c.1565T>C	p.Val522Ala	missense	Exon 12 of 12	ENSP00000363965.1
	ALPL	ENST00000540617.5	TSL:2	c.1400T>C	p.Val467Ala	missense	Exon 11 of 11	ENSP00000442672.1

Frequencies

GnomAD3 genomes AF: 0.0805 AC: 12243 AN: 152130 Hom.: 590 Cov.: 33

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

GnomAD2 exomes AF: 0.0961 AC: 21977 AN: 228758 AF XY: 0.102

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 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.: 35 AF XY: 0.111 AC XY: 79829 AN XY: 719296

African (AFR) AF: 0.0333 AC: 1111 AN: 33406

American (AMR) AF: 0.0735 AC: 3273 AN: 44504

Ashkenazi Jewish (ASJ) AF: 0.0957 AC: 2493 AN: 26042

East Asian (EAS) AF: 0.00162 AC: 64 AN: 39574

South Asian (SAS) AF: 0.164 AC: 14125 AN: 85868

European-Finnish (FIN) AF: 0.0599 AC: 2345 AN: 39158

Middle Eastern (MID) AF: 0.0782 AC: 450 AN: 5752

European-Non Finnish (NFE) AF: 0.115 AC: 128068 AN: 1110632

Other (OTH) AF: 0.102 AC: 6114 AN: 60172

GnomAD4 genome AF: 0.0804 AC: 12247 AN: 152248 Hom.: 594 Cov.: 33 AF XY: 0.0784 AC XY: 5834 AN XY: 74454

African (AFR) AF: 0.0365 AC: 1518 AN: 41546

American (AMR) AF: 0.0757 AC: 1159 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 348 AN: 3470

East Asian (EAS) AF: 0.00329 AC: 17 AN: 5174

South Asian (SAS) AF: 0.152 AC: 736 AN: 4830

European-Finnish (FIN) AF: 0.0602 AC: 639 AN: 10606

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7494 AN: 67992

Other (OTH) AF: 0.0833 AC: 176 AN: 2114

Alfa AF: 0.0931 Hom.: 255

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:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 24, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hypophosphatasia Benign:4 Other:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Dec 10, 2024

JKU Lab, Dept of Paediatrics, Johannes Kepler University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

This missense variant is present in GnomAD 4.1 (exomes = 10.7%) and does not affect a highly conserved amino acid in a functional domain. The variant is not predicted to affect protein function (REVEL score: 0.257). Splice-prediction algorithms predict no effect on splicing. In vitro functional studies showed normal reduced ALP activity. This variant has been reported in the literature in individuals affected with ALPL-related conditions (PMID:30680361). The results of the functional testing and the applied ACMG criteria can be viewed at: https://alplmutationdatabase.jku.at/table/

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 29, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

ALPL Val522Ala (c.1565T>C) is a missense variant that changes the amino acid at residue 522 from Valine to Alanine. In silico models agree that this variant is not damaging. This variant is present at high allele frequency in population databases. In conclusion, we classify ALPL p.Val522Ala (c.1565T>C) as a benign variant.

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

not provided Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Oct 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Infantile hypophosphatasia Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Adult hypophosphatasia Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Childhood hypophosphatasia Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	7.8
DANN	Benign	0.65
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.50
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.26
Sift	Benign	0.051	T
Sift4G	Uncertain	0.046	D
Polyphen		0.0030	B
Vest4		0.057
MPC		0.49
ClinPred		0.0029	T
GERP RS		-5.6
Varity_R		0.038
gMVP		0.71
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34605986; hg19: chr1-21904131; COSMIC: COSV66375923;