rs199669988

Positions:

chr1-21564097-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5BP4BS2_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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 4 hom. )

Consequence

ALPL
NM_000478.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5

Conservation

PhyloP100: 1.48

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 Likely_benign. Variant got -1 ACMG points.

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 id is 556961.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=3}. Variant chr1-21564097-G-A is described in Lovd as [Pathogenic].

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/exons	MANE	Protein	UniProt
ALPL	NM_000478.6 linkuse as main transcript	c.529G>A	p.Ala177Thr	missense_variant	6/12	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8 linkuse as main transcript	c.529G>A	p.Ala177Thr	missense_variant	6/12	1	NM_000478.6	ENSP00000363973	P1	P05186-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000131

AC:

AN:

251080

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135770

show subpopulations

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 SAS exome

AF:

0.0000653

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.:

Cov.:

AF XY:

0.000209

AC XY:

152

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00771

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000105

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00289

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000147

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Adult hypophosphatasia

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Hypophosphatasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Dec 07, 2018

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 provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

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). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 27, 2024

Variant summary: ALPL c.529G>A (p.Ala177Thr), also reported as Ala160Thr, results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 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). 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2020

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

Uncertain significance, no assertion criteria provided

research

Department of Pediatrics, Samsung Medical Center, Samsung Medical Center

- -

Infantile hypophosphatasia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.080

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

LIST_S2

Uncertain

0.86

.;D;D;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

0.88

L;.;.;L

MutationTaster

Benign

0.96

D;D;D;D;D

PrimateAI

Benign

0.46

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

GERP RS

2.0

Varity_R

0.094

gMVP

0.92

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