rs199669988

Variant names:

• chr1-21564097-G-A
• rs199669988
• NM_000478.6:c.529G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-21564097-G-A
• chr1-21564097-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PM1 PM5 PP2 PP5 BP4 BS2_Supporting

The NM_000478.6(ALPL):​c.529G>A​(p.Ala177Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,614,044 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A177V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (4 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:5
• Conservation: PhyloP100: 1.48
• Publications: 12 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000478.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-21564098-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 427764.
• 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.
• PP5: Variant 1-21564097-G-A is Pathogenic according to our data. Variant chr1-21564097-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 556961.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10656512). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6	c.529G>A	p.Ala177Thr	missense_variant	Exon 6 of 12	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8	c.529G>A	p.Ala177Thr	missense_variant	Exon 6 of 12	1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000131 AC: 33 AN: 251080 AF XY: 0.000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00158

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000220 AC: 321 AN: 1461756 Hom.: 4 Cov.: 32 AF XY: 0.000209 AC XY: 152 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

East Asian (EAS) AF: 0.00771 AC: 306 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111990

Other (OTH) AF: 0.0000497 AC: 3 AN: 60392

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74452

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000132 AC: 16

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Adult hypophosphatasia Pathogenic:1 Uncertain:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 03, 2022

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Childhood hypophosphatasia;C0268412:Infantile hypophosphatasia;C0268413:Adult hypophosphatasia Pathogenic:1

Apr 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Aug 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 177 of the ALPL protein (p.Ala177Thr). This variant is present in population databases (rs199669988, gnomAD 0.2%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 9452105, 11760847). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Ala160Thr. ClinVar contains an entry for this variant (Variation ID: 556961). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects ALPL function (PMID: 11760847, 12162492, 18455459). For these reasons, this variant has been classified as Pathogenic. -

Hypophosphatasia Pathogenic:1

Dec 07, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ALPL c.529G>A (p.Ala177Thr) missense variant, also known as p.Ala160Thr, has been reported in at least five studies in which it was found in a homozygous state in one individual with hypophosphatasia and in a compound heterozygous state in six individuals, including one individual with a milder adult-onset form of the disease and five individuals with the more severe infantile- or childhood-onset form of the disease (Goseki-Sone et al. 1998; Orimo et al. 2001; Beck et al. 2009; Collmann et al. 2009; Nair et al. 2018). The parents of three of the individuals with the childhood-onset form were shown to carry the p.Ala177Thr variant in a heterozygous state; these individuals were described as healthy but exhibited reduced serum alkaline phosphatase activity (Orimo et al. 2001). The p.Ala177Thr variant was absent from 111 controls (Goseki-Sone et al. 1998) and is reported at a frequency of 0.00174 in the East Asian population of the Exome Aggregation Consortium. In vitro functional studies conducted in several different cell lines suggest that the p.Ala177Thr variant does not affect protein expression relative to wild type but does have a moderate effect on protein function (Orimo et al. 2001; Di Mauro et al. 2002; Orimo et al. 2008). Based on the collective evidence, the p.Ala177Thr variant is classified as pathogenic for hypophosphatasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not specified Uncertain:1

May 21, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ALPL c.529G>A (p.Ala177Thr) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00021 in 1614044 control chromosomes, predominantly at a frequency of 0.0072 within the East Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2.036 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALPL causing Hypophosphatasia phenotype (0.0035).Further, this variant was observed in 30/2418 control chromosomes among individuals of Japanese descent in the Human Genetic Variation Database (HGVD), which corresponds to a 0.0124 allele frequency and is approximately 3.54 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALPL causing Hypophosphatasia phenotype (0.0035). c.529G>A has been reported in the literature in the compound-, presumed compound heterozygous or heterozygous state in multiple individuals affected with clinical or biochemical features of autosomal dominant or autosomal recessive Hypophosphatasia (example, Goseki-Sone_1998, Orimo_2001, Collmann_2009, Li_2023, Sugiyama_2022, Yoon_2020, Beck_2011), including at least 1 individual with low serum ALP who carried this variant de novo (example, Yoon_2020). Multiple affected individuals with childhood onset recessive hypophosphatasia also carried likely pathogenic/pathogenic variants in trans which were inherited from relatively healthy parents with low serum ALP levels (example, Orimo_2001). While the population frequency of this variant is not compatible with isolated cases of high-penetrance, early onset hypophosphatasia, due to the presence of multiple affected individuals with distinct pathogenic variants in trans we cannot rule out the possibility of low penetrance or hypomorphic allele status. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 81% of normal activity (example, delAngel_2020). The following publications have been ascertained in the context of this evaluation (PMID: 20383509, 18769927, 32160374, 12162492, 9452105, 37107680, 33452237, 31857675, 11760847, 18455459, 25023282, 35197081, 31754721). ClinVar contains an entry for this variant (Variation ID: 556961). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Inborn genetic diseases Uncertain:1

Oct 30, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.529G>A (p.A177T) alteration is located in exon 6 (coding exon 5) of the ALPL gene. This alteration results from a G to A substitution at nucleotide position 529, causing the alanine (A) at amino acid position 177 to be replaced by a threonine (T). Based on data from the Genome Aggregation Database (gnomAD) database, the ALPL c.529G>A alteration was observed in 0.01% (35/282450) of total alleles studied, with a frequency of 0.15% (30/19950) in the East Asian subpopulation. This variant, reported as 507G>A, was identified in a Japanese adult with hypophosphatasia and a second ALPL variant confirmed in trans (Goseki-Sone, 1998). It was also detected in three German children with hypophosphatasia (reported as p.A160T), each with a second ALPL variant confirmed in trans (Orimo, 2001). This amino acid position is not well conserved and threonine is a reference amino acid in several species. Functional studies in COS1 cells demonstrated a reduction in alkaline phosphatase activity to ~80% of wild type (Orimo, 2001; Orimo, 2008; Del Angel, 2020). The in silico prediction for the p.A177T alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Microcephaly Uncertain:1

-

Department of Pediatrics, Samsung Medical Center, Samsung Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Infantile hypophosphatasia Uncertain:1

Mar 08, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	8.8
DANN	Benign	0.21
DEOGEN2	Uncertain	0.59	D;.;.;D
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.70
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	.;D;D;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.88	L;.;.;L
PhyloP100		1.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.12	N;N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.70	T;T;T;T
Sift4G	Benign	0.80	T;T;T;T
Polyphen		0.14	B;.;.;B
Vest4		0.77
MVP		0.83
MPC		0.46
ClinPred		0.029	T
GERP RS		2.0
Varity_R		0.094
gMVP		0.92
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs199669988; hg19: chr1-21890590; COSMIC: COSV66379484;