rs2275376

chr1-21570425-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000478.6(ALPL):c.862+51G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,578,162 control chromosomes in the GnomAD database, including 21,470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3142 hom., cov: 33)
  • Exomes 𝑓: 0.14 (18328 hom.)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.34

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-21570425-G-A is Benign according to our data. Variant chr1-21570425-G-A is described in ClinVar as [Benign]. Clinvar id is 1177589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21570425-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6	c.862+51G>A		intron_variant		ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.862+51G>A		intron_variant		1	NM_000478.6	P1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27964 AN: 151924 Hom.: 3128 Cov.: 33

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.178

GnomAD3 exomes AF: 0.183 AC: 44585 AN: 244254 Hom.: 5093 AF XY: 0.177 AC XY: 23454 AN XY: 132244

Gnomad AFR exome AF: 0.260

Gnomad AMR exome AF: 0.249

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.439

Gnomad SAS exome AF: 0.214

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.141 AC: 200929 AN: 1426120 Hom.: 18328 Cov.: 28 AF XY: 0.142 AC XY: 100921 AN XY: 711124

Gnomad4 AFR exome AF: 0.269

Gnomad4 AMR exome AF: 0.245

Gnomad4 ASJ exome AF: 0.138

Gnomad4 EAS exome AF: 0.511

Gnomad4 SAS exome AF: 0.217

Gnomad4 FIN exome AF: 0.176

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.155

GnomAD4 genome AF: 0.184 AC: 28016 AN: 152042 Hom.: 3142 Cov.: 33 AF XY: 0.192 AC XY: 14255 AN XY: 74326

Gnomad4 AFR AF: 0.255

Gnomad4 AMR AF: 0.225

Gnomad4 ASJ AF: 0.140

Gnomad4 EAS AF: 0.453

Gnomad4 SAS AF: 0.233

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.182

Alfa AF: 0.141 Hom.: 330

Bravo AF: 0.192

Asia WGS AF: 0.327 AC: 1137 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile hypophosphatasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Adult hypophosphatasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Childhood hypophosphatasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.10
Dann	Benign	0.38

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: rs2275376; hg19: chr1-21896918; COSMIC: COSV66376174; COSMIC: COSV66376174;