rs786204530

chr1-21563212-AC-CA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_Moderate PM1 PM5 PP5_Very_Strong

The NM_000478.6(ALPL):c.400_401delinsCA(p.Thr134His) variant causes a missense change. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T134N) 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:5 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 14 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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000478.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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/exons	MANE	UniProt
ALPL	NM_000478.6	c.400_401delinsCA	p.Thr134His	missense_variant	5/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.400_401delinsCA	p.Thr134His	missense_variant	5/12	1	NM_000478.6	P1

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:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2023	Published functional studies demonstrate the variant abolishes enzyme activity (Cundy et al., 2015); In silico analysis supports that this variant does not alter protein structure/function; Missense variants in nearby residues reported in the Human Gene Mutation Database in individuals with hypophosphatasia (HGMD); This variant is associated with the following publications: (PMID: 25736332, 31969353, 17253930, 18386808, 19335222, 21956185, 11855933, 17409132, 18925618, 28401263, 30115096, 30719581, 32160374) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 03, 2022

- -

Infantile hypophosphatasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

literature only

Counsyl

Jul 10, 2014

- -

Adult hypophosphatasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 04, 2023

- -

Hypophosphatemia Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

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;