chr1-21561126-C-T

Position:

• chr1-21561126-C-T

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.211C>T​(p.Arg71Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,640 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. R71H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.72

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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr1-21561127-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1070177.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 1-21561126-C-T is Pathogenic according to our data. Variant chr1-21561126-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21561126-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6	c.211C>T	p.Arg71Cys	missense_variant	4/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.211C>T	p.Arg71Cys	missense_variant	4/12	1	NM_000478.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460640 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726480

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000454 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile hypophosphatasia Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 15, 1992	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 15, 2018	- -

ALPL-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2024

The ALPL c.211C>T variant is predicted to result in the amino acid substitution p.Arg71Cys. This variant in the heterozygous or along with a second variant in this gene has been reported in multiple individuals with hypophosphatasia (reported as Arg54Cys, Henthorn et al. 1992. PubMed ID: 1409720; Fauvert et al. 2009. PubMed ID: 19500388; Whyte et al. 2015. PubMed ID: 25731960; https://alplmutationdatabase.jku.at/table/). Different variants affecting the same amino acid (p.Arg71Ser, p.Arg71Gly, p.Arg71His, and p.Arg71Pro) have also been reported to be pathogenic (https://alplmutationdatabase.jku.at/table/; Human Gene Mutation Database; Whyte et al. 2015. PubMed ID: 25731960). Functional studies suggest that this variant leads to reduced alkaline phosphatase activity (Del Angel. 2020. PubMed ID: 32160374). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Adult hypophosphatasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 19, 2023

- -

Hypophosphatasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 18, 2024

Variant summary: ALPL c.211C>T (p.Arg71Cys) 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 247944 control chromosomes. c.211C>T has been reported in the literature in individuals affected with Autosomal Recessive Hypophosphatasia and autosomal dominant odonto type Hypophosphatasia (Henthorn_1992, Okawa_2019). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in diminished normal activity of ALPL in COS-1 cells (Fukushi-Irie_2000). A dominant-negative effect was also suggested in COS-7 cells (Fauvert_2009). Several different variant affecting the same codon has been classified as Pathogenic or Likely Pathogenic in ClinVar (c.211C>G p.Arg71Gly, c.211C>A p.Arg71Ser, c.212G>A p.Arg71His, c.212G>C p.Arg71Pro, c.1262C>T p.Ala421Val), supporting the critical relevance of codon 71 to ALPL protein function. The following publications have been ascertained in the context of this evaluation (PMID: 19500388, 10839996, 1409720, 31600233). ClinVar contains an entry for this variant (Variation ID: 13663). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 71 of the ALPL protein (p.Arg71Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hypophosphatasia (PMID: 1409720, 31600233). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Arg54Cys. ClinVar contains an entry for this variant (Variation ID: 13663). 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: 10839996). This variant disrupts the p.Arg71 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11438998, 22322541, 22397652, 25731960, 31760938). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	1.0	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.7	H;.;H
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.6	D;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.90
MutPred		0.99		Loss of methylation at R71 (P = 0.0251);.;Loss of methylation at R71 (P = 0.0251);
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs121918001; hg19: chr1-21887619;