1-21568201-G-T

Position:

• chr1-21568201-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5 PP3_Strong PP5_Very_Strong

The NM_000478.6(ALPL):​c.746G>T​(p.Gly249Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,988 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G249A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 U:1
• Conservation: PhyloP100: 5.35

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.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-21568200-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1009296.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 1-21568201-G-T is Pathogenic according to our data. Variant chr1-21568201-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 13682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21568201-G-T is described in Lovd as [Likely_pathogenic]. Variant chr1-21568201-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6	c.746G>T	p.Gly249Val	missense_variant	7/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.746G>T	p.Gly249Val	missense_variant	7/12	1	NM_000478.6	P1
ALPL	ENST00000374832.5	c.746G>T	p.Gly249Val	missense_variant	7/12	2		P1
ALPL	ENST00000540617.5	c.581G>T	p.Gly194Val	missense_variant	6/11	2
ALPL	ENST00000539907.5	c.515G>T	p.Gly172Val	missense_variant	5/10	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251394 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727238

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74294

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000277 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2022	Observed heterozygous with no other ALPL variants in patients with mild or childhood hypophosphatasia (Lia-Baldini et al., 2001; Fauvert et al., 2009); Published functional studies demonstrate a damaging effect due to reduction of enzyme activity and aberrant localization (Brun-Heath et al., 2007; Fauvert et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19500388, 17719863, 18340466, 11479741, 30655187, 21956185, 29236161, 31485555, 28663156, 10094560, 32160374) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 249 of the ALPL protein (p.Gly249Val). This variant is present in population databases (rs121918018, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal dominant and recessive hypophosphatasia (PMID: 10094560, 11479741, 28663156). 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 Gly232Val. ClinVar contains an entry for this variant (Variation ID: 13682). 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: 17719863, 18340466). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 17, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Childhood hypophosphatasia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 02, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2008	- -

Hypophosphatasia Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 06, 2023	Variant summary: ALPL c.746G>T (p.Gly249Val) 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 allele was found at a frequency of 4e-06 in 251394 control chromosomes. c.746G>T has been reported in the literature in multiple individuals affected with Hypophosphatasia, Autosomal Recessive, either at a homozygous state or along with a second pathogenic variant (examples, Saglam_2017, DelAngel_2020). This variant has also been reported as a sole heterozygous change in at-least two patients with Hypophosphatasia (examples, Saglam_2017, DelAngel_2020). These data indicate that the variant is very likely to be associated with disease. ALPL has been described in association with both autosomal recessive moderate hypophosphatasia and autosomal dominant mild hypophosphatasia (PMID:29236161). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity and the variant protein has failed to locate on cellular membrane (BrunHeath_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17719863, 32160374, 28663156). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (PATH, n=5, VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

ALPL-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This variant has been previously reported as a heterozygous and homozygous change in individuals with ALPL-related disorders (PMID: 19500388, 28663156, 33069919). Asymptomatic carriers of the c.746G>T (p.Gly249Val) variant have been also reported (PMID: 28663156). Functional studies have shown that this variant results in abnormal ALPL protein function (PMID: 17719863, 18340466). The c.746G>T (p.Gly249Val) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/251394). The c.746G>T (p.Gly249Val) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.746G>T (p.Gly249Val) variant is classified as Pathogenic. -

Adult hypophosphatasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 20, 2024

- -

Odontohypophosphatasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2008

- -

Infantile hypophosphatasia Uncertain:1

Uncertain significance, flagged submission

clinical testing

Counsyl

Jun 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.;D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.;.;H
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-6.2	D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.71
MutPred		0.89		Loss of helix (P = 0.0017);.;.;Loss of helix (P = 0.0017);
MVP		0.98
MPC		1.4
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.95
gMVP		0.94

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

Other links and lift over

dbSNP: rs121918018; hg19: chr1-21894694;