rs121918009

chr1-21575736-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000478.6(ALPL):c.1001G>A(p.Gly334Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G334S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 9.94

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 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr1-21575735-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1932270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 1-21575736-G-A is Pathogenic according to our data. Variant chr1-21575736-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21575736-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6	c.1001G>A	p.Gly334Asp	missense_variant	10/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.1001G>A	p.Gly334Asp	missense_variant	10/12	1	NM_000478.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 334 of the ALPL protein (p.Gly334Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypophosphatasia (PMID: 8406453, 24569605). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gly317Asp. ClinVar contains an entry for this variant (Variation ID: 13672). 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%. Experimental studies have shown that this missense change affects ALPL function (PMID: 19500388, 24569605). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 04, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2021	Not observed in large population cohorts (Lek et al., 2016); Published functional studies demonstrate this variant has decreased activity and dominant-negative effects (Fauvert et al., 2009; Hoffman et al., 2014; Del Angel et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8406453, 33101980, 24569605, 19500388, 32160374, 20301329, 9618260, 9781036, 12638946, 15694177, 22397652) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2019	- -

Hypophosphatasia Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 05, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 23, 2024	Variant summary: ALPL c.1001G>A (p.Gly334Asp, also known as p.Gly317Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250928 control chromosomes. c.1001G>A has been reported either at a homozygous state or at a compound heterozygous state along with a second pathogenic variant in multiple individuals affected with autosomal recessive Hypophosphatasia (example, DelAngel_2020, Gehring_1999). 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. The most pronounced variant effect results in about 6% of normal activity in MDCK II cells (DelAngel_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32160374, 10636450). ClinVar contains an entry for this variant (Variation ID: 13672). Based on the evidence outlined above, the variant was classified as pathogenic. -

Infantile hypophosphatasia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 23, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1993	- -

Adult hypophosphatasia Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Dec 12, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 30, 2022	- -

Osteogenesis imperfecta Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 01, 2020

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

ALPL-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 27, 2023

The ALPL c.1001G>A variant is predicted to result in the amino acid substitution p.Gly334Asp. This variant is a common pathogenic variant in the Canadian Mennonite population and has been reported in several Mennonite patients with hypophosphatasia (HPP) (Greenberg et al. 1993. PubMed ID: 8406453, reported as p.Gly317Asp). This variant has also been reported in the homozygous or compound heterozygous state in several other unrelated patients with HPP (Orimo et al. 2002. PubMed ID: 12638946; Mornet et al. 1998. PubMed ID: 9781036; Hofmann et al. 2014. PubMed ID: 24569605). Functional studies support its pathogenicity (Fauvert et al. 2009. PubMed ID: 19500388; Hofmann et al. 2014. PubMed ID: 24569605; Del Angel et al. 2020. PubMed ID: 32160374). A different substitution (Gly334Arg), affecting the same amino acid residue, was reported in a patient with mild HPP (Fauvert et al. 2009. PubMed ID: 19500388). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	1.0	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;.;.;H
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.1	D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.99
MutPred		0.95		Gain of loop (P = 0.0312);.;.;Gain of loop (P = 0.0312);
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.96
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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

Other links and lift over

dbSNP: rs121918009; hg19: chr1-21902229;