rs1256335

Positions:

• chr1-21563893-G-A
• chr1-21563893-G-C

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.473-148G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 997,492 control chromosomes in the GnomAD database, including 317,948 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (48679 hom., cov: 27)
  • Exomes 𝑓: 0.80 (269269 hom.)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.57

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=-0.91).
• BP6: Variant 1-21563893-G-A is Benign according to our data. Variant chr1-21563893-G-A is described in ClinVar as [Benign]. Clinvar id is 1188974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6	c.473-148G>A		intron_variant		ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.473-148G>A		intron_variant		1	NM_000478.6	P1

Frequencies

GnomAD3 genomes AF: 0.801 AC: 121136 AN: 151208 Hom.: 48637 Cov.: 27

Gnomad AFR AF: 0.773

Gnomad AMI AF: 0.848

Gnomad AMR AF: 0.850

Gnomad ASJ AF: 0.855

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.812

Gnomad FIN AF: 0.803

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.811

GnomAD4 exome AF: 0.796 AC: 673192 AN: 846166 Hom.: 269269 AF XY: 0.796 AC XY: 343369 AN XY: 431334

Gnomad4 AFR exome AF: 0.766

Gnomad4 AMR exome AF: 0.869

Gnomad4 ASJ exome AF: 0.857

Gnomad4 EAS exome AF: 0.988

Gnomad4 SAS exome AF: 0.795

Gnomad4 FIN exome AF: 0.807

Gnomad4 NFE exome AF: 0.779

Gnomad4 OTH exome AF: 0.805

GnomAD4 genome AF: 0.801 AC: 121228 AN: 151326 Hom.: 48679 Cov.: 27 AF XY: 0.807 AC XY: 59589 AN XY: 73860

Gnomad4 AFR AF: 0.773

Gnomad4 AMR AF: 0.850

Gnomad4 ASJ AF: 0.855

Gnomad4 EAS AF: 0.984

Gnomad4 SAS AF: 0.811

Gnomad4 FIN AF: 0.803

Gnomad4 NFE AF: 0.789

Gnomad4 OTH AF: 0.812

Alfa AF: 0.791 Hom.: 67955

Bravo AF: 0.801

Asia WGS AF: 0.874 AC: 3038 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Childhood hypophosphatasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.19
DANN	Benign	0.54

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: rs1256335; hg19: chr1-21890386; COSMIC: COSV66379633;