rs786204530

Variant names:

• chr1-21563212-AC-CA
• rs786204530
• NM_000478.6:c.400_401delACinsCA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1_Moderate PM1 PM2 PM5 PP5_Very_Strong

The NM_000478.6(ALPL):​c.400_401delACinsCA​(p.Thr134His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T134S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 6.64

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PS1: Transcript NM_000478.6 (ALPL) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000478.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-21563213-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3633517.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 1-21563212-AC-CA is Pathogenic according to our data. Variant chr1-21563212-AC-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6	c.400_401delACinsCA	p.Thr134His	missense_variant		ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8	c.400_401delACinsCA	p.Thr134His	missense_variant		1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Mar 14, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate the variant abolishes enzyme activity (PMID: 25736332); Missense variants in nearby residues reported in the Human Gene Mutation Database in individuals with hypophosphatasia (HGMD); In silico analysis indicates that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25736332, 31969353, 17253930, 18386808, 19335222, 21956185, 11855933, 17409132, 18925618, 28401263, 30115096, 30719581, 32160374, 34633109) -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with histidine, which is basic and polar, at codon 134 of the ALPL protein (p.Thr134His). This variant is present in population databases (rs786204530, gnomAD 0.005%). This missense change has been observed in individual(s) with autosomal recessive hypophosphatasia and hypophosphatasia (PMID: 11855933, 17409132, 18386808, 18925618, 19335222). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Thr117His. ClinVar contains an entry for this variant (Variation ID: 188877). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

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

Apr 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Infantile hypophosphatasia Pathogenic:1

Jul 10, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Adult hypophosphatasia Pathogenic:1

Mar 13, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypophosphatasia Pathogenic:1

Apr 18, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ALPL c.400_401delinsCA (p.Thr134His) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 250968 control chromosomes (gnomAD). c.400_401delinsCA has been reported in the literature in multiple individuals affected with Hypophosphatasia (e.g. del Angel_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in 10%-<30% of normal enzymatic activity (del Angel_2020). The following publication has been ascertained in the context of this evaluation (PMID: 32160374). ClinVar contains an entry for this variant (Variation ID: 188877). Based on the evidence outlined above, the variant was classified as pathogenic. -

Hypophosphatemia Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as pathogenic and reported on 07/24/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786204530; hg19: chr1-21889705;