rs1256328

Positions:

• chr1-21570274-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.793-31C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,610,114 control chromosomes in the GnomAD database, including 21,467 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1609 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19858 hom.)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.10

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 1-21570274-C-T is Benign according to our data. Variant chr1-21570274-C-T is described in ClinVar as [Benign]. Clinvar id is 256232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21570274-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALPL	NM_000478.6	c.793-31C>T		intron_variant		ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8	c.793-31C>T		intron_variant		1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21420 AN: 152068 Hom.: 1602 Cov.: 32

Gnomad AFR AF: 0.0947

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.163

GnomAD3 exomes AF: 0.162 AC: 40526 AN: 250202 Hom.: 3437 AF XY: 0.166 AC XY: 22500 AN XY: 135278

Gnomad AFR exome AF: 0.0970

Gnomad AMR exome AF: 0.140

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.195

Gnomad SAS exome AF: 0.206

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.163 AC: 237261 AN: 1457928 Hom.: 19858 Cov.: 31 AF XY: 0.164 AC XY: 119111 AN XY: 725528

Gnomad4 AFR exome AF: 0.0965

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.220

Gnomad4 EAS exome AF: 0.178

Gnomad4 SAS exome AF: 0.203

Gnomad4 FIN exome AF: 0.109

Gnomad4 NFE exome AF: 0.163

Gnomad4 OTH exome AF: 0.166

GnomAD4 genome AF: 0.141 AC: 21437 AN: 152186 Hom.: 1609 Cov.: 32 AF XY: 0.139 AC XY: 10348 AN XY: 74410

Gnomad4 AFR AF: 0.0950

Gnomad4 AMR AF: 0.148

Gnomad4 ASJ AF: 0.224

Gnomad4 EAS AF: 0.180

Gnomad4 SAS AF: 0.186

Gnomad4 FIN AF: 0.106

Gnomad4 NFE AF: 0.160

Gnomad4 OTH AF: 0.165

Alfa AF: 0.167 Hom.: 4622

Bravo AF: 0.145

Asia WGS AF: 0.178 AC: 621 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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	-0.88
CADD	Benign	1.8
DANN	Benign	0.47

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: rs1256328; hg19: chr1-21896767;