rs1553414079

Variant names:

• chr1-21573682-G-A
• NM_000478.6:c.880G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-21573682-G-A
• chr1-21573682-G-C
• chr1-21573682-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000478.6(ALPL):​c.880G>A​(p.Asp294Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D294A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.48

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 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr1-21573683-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 13664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• PP5: Variant 1-21573682-G-A is Pathogenic according to our data. Variant chr1-21573682-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2890088.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6	c.880G>A	p.Asp294Asn	missense_variant	Exon 9 of 12	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8	c.880G>A	p.Asp294Asn	missense_variant	Exon 9 of 12	1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Mar 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 294 of the ALPL protein (p.Asp294Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypophosphatasia (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ALPL protein function with a positive predictive value of 95%. This variant disrupts the p.Asp294 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1409720, 15694177, 19335222, 22397652, 25731960). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

ALPL-related disorder Uncertain:1

Jun 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ALPL c.880G>A variant is predicted to result in the amino acid substitution p.Asp294Asn. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Different variants affecting the same amino acid (p.Asp294Ala and p.Asp294Tyr) were reported in individuals with hypophosphatasia (Taillandier et al. 2001. PubMed ID: 11438998; Warren. 2021. PubMed ID: 34515659, https://alplmutationdatabase.jku.at/table/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.2	L;.;.;L
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Pathogenic	0.74
Sift	Benign	0.068	T;T;T;T
Sift4G	Benign	0.41	T;T;T;T
Polyphen		0.99	D;.;.;D
Vest4		0.84
MutPred		0.62		Gain of catalytic residue at D294 (P = 0.1422);.;.;Gain of catalytic residue at D294 (P = 0.1422);
MVP		0.98
MPC		1.2
ClinPred		0.97	D
GERP RS		3.9
Varity_R		0.48
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-21900175;