rs2242420

chr1-21578036-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000478.6(ALPL):c.*388C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 288,568 control chromosomes in the GnomAD database, including 1,923 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1056 hom., cov: 33)
  • Exomes 𝑓: 0.099 (867 hom.)
• Consequence: ALPL NM_000478.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.869

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 1-21578036-C-T is Benign according to our data. Variant chr1-21578036-C-T is described in ClinVar as [Benign]. Clinvar id is 295566.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6	c.*388C>T		3_prime_UTR_variant	12/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.*388C>T		3_prime_UTR_variant	12/12	1	NM_000478.6	P1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17575 AN: 152140 Hom.: 1056 Cov.: 33

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.0689

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.140

GnomAD4 exome AF: 0.0989 AC: 13478 AN: 136308 Hom.: 867 Cov.: 0 AF XY: 0.0967 AC XY: 6843 AN XY: 70790

Gnomad4 AFR exome AF: 0.0959

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.154

Gnomad4 EAS exome AF: 0.167

Gnomad4 SAS exome AF: 0.0582

Gnomad4 FIN exome AF: 0.0978

Gnomad4 NFE exome AF: 0.0972

Gnomad4 OTH exome AF: 0.108

GnomAD4 genome AF: 0.115 AC: 17577 AN: 152260 Hom.: 1056 Cov.: 33 AF XY: 0.115 AC XY: 8553 AN XY: 74458

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.191

Gnomad4 SAS AF: 0.0689

Gnomad4 FIN AF: 0.113

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.138

Alfa AF: 0.122 Hom.: 1576

Bravo AF: 0.119

Asia WGS AF: 0.107 AC: 372 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypophosphatasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	2.7
Dann	Benign	0.77

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: rs2242420; hg19: chr1-21904529; COSMIC: COSV66376684; COSMIC: COSV66376684;