rs1780329

chr1-21576457-C-Achr1-21576457-C-T

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.1190-65C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,585,492 control chromosomes in the GnomAD database, including 36,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5390 hom., cov: 31)
  • Exomes 𝑓: 0.19 (30678 hom.)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.873

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=-0.84).
• BP6: Variant 1-21576457-C-A is Benign according to our data. Variant chr1-21576457-C-A is described in ClinVar as [Benign]. Clinvar id is 1177605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6	c.1190-65C>A		intron_variant		ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.1190-65C>A		intron_variant		1	NM_000478.6	P1

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37615 AN: 151688 Hom.: 5377 Cov.: 31

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.469

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.236

GnomAD4 exome AF: 0.195 AC: 279081 AN: 1433684 Hom.: 30678 AF XY: 0.195 AC XY: 138347 AN XY: 709848

Gnomad4 AFR exome AF: 0.350

Gnomad4 AMR exome AF: 0.278

Gnomad4 ASJ exome AF: 0.157

Gnomad4 EAS exome AF: 0.524

Gnomad4 SAS exome AF: 0.248

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.168

Gnomad4 OTH exome AF: 0.209

GnomAD4 genome AF: 0.248 AC: 37670 AN: 151808 Hom.: 5390 Cov.: 31 AF XY: 0.254 AC XY: 18830 AN XY: 74202

Gnomad4 AFR AF: 0.350

Gnomad4 AMR AF: 0.278

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.470

Gnomad4 SAS AF: 0.257

Gnomad4 FIN AF: 0.268

Gnomad4 NFE AF: 0.166

Gnomad4 OTH AF: 0.241

Alfa AF: 0.180 Hom.: 2608

Bravo AF: 0.253

Asia WGS AF: 0.356 AC: 1238 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	-0.84
Cadd	Benign	1.5
Dann	Benign	0.75

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: rs1780329; hg19: chr1-21902950; COSMIC: COSV66376181;