1-21577578-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BP4_Strong

The NM_000478.6(ALPL):c.1505C>T(p.Ser502Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000643 in 1,602,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S502S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 0.690

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_benign. Variant got -2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000478.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.02999559).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6	c.1505C>T	p.Ser502Leu	missense_variant	12/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.1505C>T	p.Ser502Leu	missense_variant	12/12	1	NM_000478.6	P1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000101 AC: 24 AN: 238082 Hom.: 0 AF XY: 0.0000689 AC XY: 9 AN XY: 130614

Gnomad AFR exome AF: 0.000718

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.0000657

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000272

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000510 AC: 74 AN: 1450636 Hom.: 0 Cov.: 32 AF XY: 0.0000374 AC XY: 27 AN XY: 722224

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74494

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000281 Hom.: 0

Bravo AF: 0.000272

ExAC AF: 0.0000744 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 08, 2021	The ALPL c.1505C>T; p.Ser502Leu variant (rs550358395), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 585385). This variant is found in the general population with an overall allele frequency of 0.012% (33/269432 alleles) in the Genome Aggregation Database. The serine at codon 502 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.186). Due to limited information, the clinical significance of the p.Ser502Leu variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 08, 2022	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 502 of the ALPL protein (p.Ser502Leu). This variant is present in population databases (rs550358395, gnomAD 0.08%). This missense change has been observed in individual(s) with hypophosphatasia (Invitae). ClinVar contains an entry for this variant (Variation ID: 585385). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 20, 2021

- -

Hypophosphatasia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 28, 2019

- -

Osteogenesis imperfecta Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.37	T;.;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.21	N
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.030	T;T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.69	N;.;.;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.076	T;D;D;T
Sift4G	Uncertain	0.044	D;D;D;D
Polyphen		0.0	B;.;.;B
Vest4		0.056
MVP		0.81
MPC		0.48
ClinPred		0.016	T
GERP RS		-0.37
Varity_R		0.095
gMVP		0.47

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: rs550358395; hg19: chr1-21904071;