1-21577615-G-T

Position:

chr1-21577615-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_000478.6(ALPL):c.1542G>T(p.Ala514=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,599,578 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A514A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0082 ( 10 hom., cov: 32)

Exomes 𝑓: 0.011 ( 108 hom. )

Consequence

ALPL
NM_000478.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.150

Variant links:

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]

ALPL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 1-21577615-G-T is Benign according to our data. Variant chr1-21577615-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 256229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21577615-G-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.15 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6 linkuse as main transcript	c.1542G>T	p.Ala514=	synonymous_variant	12/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8 linkuse as main transcript	c.1542G>T	p.Ala514=	synonymous_variant	12/12	1	NM_000478.6	P1	P05186-1

Frequencies

GnomAD3 genomes

AF:

0.00817

AC:

1244

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.0209

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00579

Gnomad FIN

AF:

0.0189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0124

Gnomad OTH

AF:

0.00622

GnomAD3 exomes

AF:

0.00841

AC:

1964

AN:

233578

Hom.:

AF XY:

0.00865

AC XY:

1111

AN XY:

128458

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00249

Gnomad ASJ exome

AF:

0.00659

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00733

Gnomad FIN exome

AF:

0.0176

Gnomad NFE exome

AF:

0.0121

Gnomad OTH exome

AF:

0.00729

GnomAD4 exome

AF:

0.0110

AC:

15907

AN:

1447266

Hom.:

108

Cov.:

AF XY:

0.0109

AC XY:

7837

AN XY:

720518

show subpopulations

Gnomad4 AFR exome

AF:

0.00138

Gnomad4 AMR exome

AF:

0.00271

Gnomad4 ASJ exome

AF:

0.00629

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00787

Gnomad4 FIN exome

AF:

0.0167

Gnomad4 NFE exome

AF:

0.0124

Gnomad4 OTH exome

AF:

0.00798

GnomAD4 genome

AF:

0.00817

AC:

1244

AN:

152312

Hom.:

Cov.:

AF XY:

0.00823

AC XY:

613

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00188

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00579

Gnomad4 FIN

AF:

0.0189

Gnomad4 NFE

AF:

0.0124

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00945

Hom.:

Bravo

AF:

0.00632

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00992

EpiControl

AF:

0.00921

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	ALPL: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 13, 2018	Variant summary: ALPL c.1542G>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0089 in 260566 control chromosomes, predominantly within the Finnish subpopulation at a frequency of 0.018, including 5 homozygotes (in the gnomAD database). The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALPL causing Hypophosphatasia phenotype (0.0035), strongly suggesting that the variant is a benign polymorphism. c.1542G>T has been reported in the literature in individuals affected with Hypophosphatasia but it was also found in normal controls (Nielson 2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hypophosphatasia

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -

Osteogenesis imperfecta

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.95

DANN

Benign

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over