1-21554110-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_000478.6(ALPL):c.29T>C(p.Ile10Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,397,648 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.96

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000478.6
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-21554110-T-C is Pathogenic according to our data. Variant chr1-21554110-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2573417.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-21554110-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6	c.29T>C	p.Ile10Thr	missense_variant	2/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.29T>C	p.Ile10Thr	missense_variant	2/12	1	NM_000478.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251484 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1397648 Hom.: 0 Cov.: 33 AF XY: 0.00000432 AC XY: 3 AN XY: 694524

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000866

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypophosphatasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jun 06, 2023

Variant summary: ALPL c.29T>C (p.Ile10Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251484 control chromosomes (gnomAD). c.29T>C has been reported in the literature as a compound heterozygous genotype and at least once in the homozygous state in individuals affected with childhood/infantile-onset autosomal recessive Hypophosphatasia (e.g. Xu_2018, Mornet_2021). These data indicate that the variant may be associated with disease. A functional study examining the effect of the variant in vitro found that it results in 29% of WT activity but does not exhibit a dominant negative effect when expressed with the WT allele (del Angel_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32160374, 32973344, 29724887). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.36	T;T
Eigen	Benign	-0.042
Eigen_PC	Benign	0.063
FATHMM_MKL	Benign	0.46	N
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.033	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.24	B;B
Vest4		0.62
MutPred		0.53		Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);
MVP		0.95
MPC		0.54
ClinPred		0.13	T
GERP RS		3.6
Varity_R		0.069
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1408044973; hg19: chr1-21880603; COSMIC: COSV66380698;