rs1780316

Positions:

chr1-21563142-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000478.6(ALPL):c.330T>C(p.Ser110Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.941 in 1,613,716 control chromosomes in the GnomAD database, including 714,982 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.93 ( 65398 hom., cov: 34)

Exomes 𝑓: 0.94 ( 649584 hom. )

Consequence

ALPL
NM_000478.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.867

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:

ALPL (HGNC:):

ALPL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 1-21563142-T-C is Benign according to our data. Variant chr1-21563142-T-C is described in ClinVar as [Benign]. Clinvar id is 197678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.867 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALPL	NM_000478.6 linkuse as main transcript	c.330T>C	p.Ser110Ser	synonymous_variant	5/12	ENST00000374840.8	NP_000469.3	P05186-1A0A024RAB4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8 linkuse as main transcript	c.330T>C	p.Ser110Ser	synonymous_variant	5/12	1	NM_000478.6	ENSP00000363973.3		P05186-1

Frequencies

GnomAD3 genomes

AF:

0.926

AC:

140906

AN:

152174

Hom.:

65340

Cov.:

show subpopulations

Gnomad AFR

AF:

0.867

Gnomad AMI

AF:

0.989

Gnomad AMR

AF:

0.953

Gnomad ASJ

AF:

0.977

Gnomad EAS

AF:

0.987

Gnomad SAS

AF:

0.956

Gnomad FIN

AF:

0.937

Gnomad MID

AF:

0.927

Gnomad NFE

AF:

0.944

Gnomad OTH

AF:

0.932

GnomAD3 exomes

AF:

0.947

AC:

237694

AN:

250932

Hom.:

112687

AF XY:

0.948

AC XY:

128711

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.865

Gnomad AMR exome

AF:

0.968

Gnomad ASJ exome

AF:

0.978

Gnomad EAS exome

AF:

0.986

Gnomad SAS exome

AF:

0.953

Gnomad FIN exome

AF:

0.938

Gnomad NFE exome

AF:

0.943

Gnomad OTH exome

AF:

0.951

GnomAD4 exome

AF:

0.943

AC:

1377566

AN:

1461424

Hom.:

649584

Cov.:

AF XY:

0.943

AC XY:

685845

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.860

Gnomad4 AMR exome

AF:

0.965

Gnomad4 ASJ exome

AF:

0.978

Gnomad4 EAS exome

AF:

0.990

Gnomad4 SAS exome

AF:

0.955

Gnomad4 FIN exome

AF:

0.937

Gnomad4 NFE exome

AF:

0.941

Gnomad4 OTH exome

AF:

0.942

GnomAD4 genome

AF:

0.926

AC:

141023

AN:

152292

Hom.:

65398

Cov.:

AF XY:

0.929

AC XY:

69138

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.867

Gnomad4 AMR

AF:

0.953

Gnomad4 ASJ

AF:

0.977

Gnomad4 EAS

AF:

0.988

Gnomad4 SAS

AF:

0.956

Gnomad4 FIN

AF:

0.937

Gnomad4 NFE

AF:

0.944

Gnomad4 OTH

AF:

0.933

Alfa

AF:

0.941

Hom.:

109441

Bravo

AF:

0.921

Asia WGS

AF:

0.970

AC:

3372

AN:

3478

EpiCase

AF:

0.946

EpiControl

AF:

0.941

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2018	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 11, 2020	The p.Ser110Ser variant in ALPL is classified as benign because it is the major allele at this position and is present in 94.5% (266754/282304) of total chromosomes in gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -

Hypophosphatasia

Benign:2

Benign, criteria provided, single submitter	clinical testing	JKU Lab, Dept of Paediatrics, Johannes Kepler University	Mar 04, 2022	GnomAD frequency 94.49%. It is a Synonymous change. Further details on the ACMG criteria applied could be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at/ -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 16, 2019	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Infantile hypophosphatasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Adult hypophosphatasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Childhood hypophosphatasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

1.2

DANN

Benign

0.32

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