chr1-21570394-G-T

Position:

• chr1-21570394-G-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.862+20G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,611,926 control chromosomes in the GnomAD database, including 21,827 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3131 hom., cov: 33)
  • Exomes 𝑓: 0.14 (18696 hom.)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.772

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=-0.9).
• BP6: Variant 1-21570394-G-T is Benign according to our data. Variant chr1-21570394-G-T is described in ClinVar as [Benign]. Clinvar id is 256233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21570394-G-T 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+20G>T		intron_variant		ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.862+20G>T		intron_variant		1	NM_000478.6	P1

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27822 AN: 151946 Hom.: 3118 Cov.: 33

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.178

GnomAD3 exomes AF: 0.183 AC: 45705 AN: 250058 Hom.: 5336 AF XY: 0.178 AC XY: 24060 AN XY: 135298

Gnomad AFR exome AF: 0.255

Gnomad AMR exome AF: 0.250

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.442

Gnomad SAS exome AF: 0.215

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.140 AC: 204817 AN: 1459862 Hom.: 18696 Cov.: 32 AF XY: 0.141 AC XY: 102701 AN XY: 726352

Gnomad4 AFR exome AF: 0.265

Gnomad4 AMR exome AF: 0.245

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.511

Gnomad4 SAS exome AF: 0.217

Gnomad4 FIN exome AF: 0.175

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.155

GnomAD4 genome AF: 0.183 AC: 27873 AN: 152064 Hom.: 3131 Cov.: 33 AF XY: 0.191 AC XY: 14174 AN XY: 74312

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.225

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.454

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.187

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.182

Alfa AF: 0.141 Hom.: 330

Bravo AF: 0.191

Asia WGS AF: 0.327 AC: 1137 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 17, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2275377; hg19: chr1-21896887; COSMIC: COSV66376057; COSMIC: COSV66376057;