rs34810399

chr1-21577454-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000478.6(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 NM_000478.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.136

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 -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 NM_000478.6
• 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6	c.1381G>A	p.Val461Ile	missense_variant	12/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.1381G>A	p.Val461Ile	missense_variant	12/12	1	NM_000478.6	P1

Frequencies

GnomAD3 genomes AF: 0.00790 AC: 1203 AN: 152188 Hom.: 23 Cov.: 33

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.: 6 AF XY: 0.00155 AC XY: 207 AN XY: 133402

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.: 13 Cov.: 33 AF XY: 0.000684 AC XY: 497 AN XY: 726086

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.: 23 Cov.: 33 AF XY: 0.00775 AC XY: 577 AN XY: 74480

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.: 6

Bravo AF: 0.00855

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0225 AC: 99

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00228 AC: 277

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 31, 2017	- -
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	- -
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. -
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/ -

Osteogenesis imperfecta Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 08, 2021

- -

ALPL-related disorder Benign:1

Likely benign, criteria provided, single submitter

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). -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	16
Dann	Benign	0.94
DEOGEN2	Uncertain	0.61	D;.;.;D
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.39	N
MetaRNN	Benign	0.0055	T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.36	N;.;.;N
MutationTaster	Benign	0.99	D;D;D;D;D;D;D
PrimateAI	Benign	0.34	T
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	T
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

Other links and lift over

dbSNP: rs34810399; hg19: chr1-21903947; COSMIC: COSV100876146;