rs34810399

Positions:

chr1-21577454-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000374840.8(ALPL):c.1381G>A(p.Val461Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,611,446 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0079 ( 23 hom., cov: 33)

Exomes 𝑓: 0.00081 ( 13 hom. )

Consequence

ALPL
ENST00000374840.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.136

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 -18 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000374840.8

BP4

Computational evidence support a benign effect (MetaRNN=0.0055370033).

BP6

Variant 1-21577454-G-A is Benign according to our data. Variant chr1-21577454-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 295552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21577454-G-A is described in Lovd as [Benign]. Variant chr1-21577454-G-A is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00792 (1207/152306) while in subpopulation AFR AF= 0.0277 (1151/41566). AF 95% confidence interval is 0.0264. There are 23 homozygotes in gnomad4. There are 577 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALPL	NM_000478.6 linkuse as main transcript	c.1381G>A	p.Val461Ile	missense_variant	12/12	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8 linkuse as main transcript	c.1381G>A	p.Val461Ile	missense_variant	12/12	1	NM_000478.6	ENSP00000363973	P1	P05186-1

Frequencies

GnomAD3 genomes

AF:

0.00790

AC:

1203

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0277

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00203

AC:

497

AN:

244718

Hom.:

AF XY:

0.00155

AC XY:

207

AN XY:

133402

show subpopulations

Gnomad AFR exome

AF:

0.0275

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000295

Gnomad FIN exome

AF:

0.0000510

Gnomad NFE exome

AF:

0.0000905

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.000806

AC:

1176

AN:

1459140

Hom.:

Cov.:

AF XY:

0.000684

AC XY:

497

AN XY:

726086

show subpopulations

Gnomad4 AFR exome

AF:

0.0265

Gnomad4 AMR exome

AF:

0.00143

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.0000197

Gnomad4 NFE exome

AF:

0.0000818

Gnomad4 OTH exome

AF:

0.00184

GnomAD4 genome

AF:

0.00792

AC:

1207

AN:

152306

Hom.:

Cov.:

AF XY:

0.00775

AC XY:

577

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0277

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00155

Hom.:

Bravo

AF:

0.00855

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0225

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00228

AC:

277

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 31, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 05, 2018	- -

Hypophosphatasia

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 10, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	JKU Lab, Dept of Paediatrics, Johannes Kepler University	Apr 09, 2024	The variant is present in GnomAD, with a reported frequency of 2.716% (f = 0.02716) in the African/African American population and an overall frequency of 0.0806% (f = 0.000806). The ACMG criteria applied can be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at/table/ -
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

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 08, 2021

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 04, 2022

Variant summary: ALPL c.1381G>A (p.Val461Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 276070 control chromosomes (gnomAD v2.1), predominantly at a frequency of 0.028 within the African or African-American subpopulation, including 11 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 8 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 found primarily in populations of African or African-American origin. At least one publication reports experimental evidence evaluating an impact on protein function, showing that the variant protein had 80% residual activity compared to the wild type (del Angel_2020). Six ClinVar submitters have assessed the variant since 2014: one classified the variant as likely benign and five as benign. Based on the evidence outlined above, the variant was classified as benign. -

ALPL-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 25, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Uncertain

0.61

D;.;.;D

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.92

.;D;D;D

MetaRNN

Benign

0.0055

T;T;T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.36

N;.;.;N

MutationTaster

Benign

0.99

D;D;D;D;D;D;D

PrimateAI

Benign

0.34

PROVEAN

Benign

0.070

N;N;N;N

REVEL

Uncertain

0.29

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.014

B;.;.;B

Vest4

0.088

MVP

0.87

MPC

0.36

ClinPred

0.0064

GERP RS

3.0

Varity_R

0.030

gMVP

0.60

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