rs1553414611

Positions:

• chr1-21575867-G-C

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.1132G>C​(p.Asp378His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 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. D378V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 9.89

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, 1 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 chr1-21575868-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 13671.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 1-21575867-G-C is Pathogenic according to our data. Variant chr1-21575867-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21575867-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6	c.1132G>C	p.Asp378His	missense_variant	10/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.1132G>C	p.Asp378His	missense_variant	10/12	1	NM_000478.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2022	Observed in heterozygyous state in a patient with benign prenatal hypophosphatasia (BP-HPP) in published literature (Wenkert et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35320273, 21713987) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 378 of the ALPL protein (p.Asp378His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe childhood hypophosphatasia (HPP) and adult HPP (PMID: 21713987). ClinVar contains an entry for this variant (Variation ID: 556746). 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.Asp378 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1409720, 10508980, 17213282, 17922851, 19335222, 19500388, 21713987, 25731960, 28580391). 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. -

Adult hypophosphatasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 01, 2023

- -

Hypophosphatasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 15, 2023

Variant summary: ALPL c.1132G>C (p.Asp378His) 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 251492 control chromosomes (gnomAD). c.1132G>C has been reported as compound heterozygous in multiple individuals affected with Hypophosphatasia (Wenkert_2011, Whyte_2015, Kishani_2021, etc.). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Xiao_2022). However, missense variants in the same residue (D378G, D378Y, D378V) have been reported in the Human Gene Mutation Database in association with Hypophosphatasia and D378V has been classified as DV in our lab, supporting the functional importance of this residue of the protein. Three ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. The variant was classified as uncertain significance (n=1), likely pathogenic (n=1), and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Infantile hypophosphatasia Uncertain:1

Uncertain significance, flagged submission

clinical testing

Counsyl

Feb 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	1.0	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.8	H;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.6	D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.99
MutPred		0.96		Loss of stability (P = 0.0571);.;.;Loss of stability (P = 0.0571);
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.97
gMVP		0.99

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: rs1553414611; hg19: chr1-21902360;