1-21554125-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6_Very_StrongBS2_Supporting

The NM_000478.6(ALPL):c.44C>G(p.Thr15Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,590,560 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict 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. T15T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00023 ( 4 hom. )

Consequence

ALPL
NM_000478.6 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.653

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:

ENSG00000289715 (HGNC:):

ENSG00000289715 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000478.6

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 220 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 1.2672 (below the threshold of 3.09). Trascript score misZ: 1.9021 (below the threshold of 3.09). GenCC associations: The gene is linked to perinatal lethal hypophosphatasia, adult hypophosphatasia, odontohypophosphatasia, childhood hypophosphatasia, hypophosphatasia, infantile hypophosphatasia.

BP4

Computational evidence support a benign effect (MetaRNN=0.009112239).

BP6

Variant 1-21554125-C-G is Benign according to our data. Variant chr1-21554125-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 740173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6 link	c.44C>G	p.Thr15Ser	missense_variant	Exon 2 of 12	ENST00000374840.8	NP_000469.3	P05186-1A0A024RAB4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8 link	c.44C>G	p.Thr15Ser	missense_variant	Exon 2 of 12	1	NM_000478.6	ENSP00000363973.3		P05186-1
ENSG00000289715	ENST00000696766.1 link	c.*123C>G		downstream_gene_variant				ENSP00000512858.1		A0A8Q3SIZ7

Frequencies

GnomAD3 genomes

AF:

0.000113

AC:

AN:

150478

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000663

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00278

Gnomad FIN

AF:

0.0000970

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000296

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000469

AC:

118

AN:

251480

AF XY:

0.000684

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000234

AC:

337

AN:

1439966

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

231

AN XY:

716070

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

32752

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

43956

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25284

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

38118

Gnomad4 SAS exome

AF:

0.00369

AC:

317

AN:

86014

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

51840

Gnomad4 NFE exome

AF:

0.0000100

AC:

AN:

1097564

Gnomad4 Remaining exome

AF:

0.000153

AC:

AN:

58832

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000113

AC:

AN:

150594

Hom.:

Cov.:

AF XY:

0.000190

AC XY:

AN XY:

73612

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.0000661

AC:

0.0000661463

AN:

0.0000661463

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00278

AC:

0.00278134

AN:

0.00278134

Gnomad4 FIN

AF:

0.0000970

AC:

0.0000969744

AN:

0.0000969744

Gnomad4 NFE

AF:

0.0000296

AC:

0.0000295744

AN:

0.0000295744

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.000576

AC:

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypophosphatasia

Benign:2

Oct 08, 2024

JKU Lab, Dept of Paediatrics, Johannes Kepler University

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing;in vitro

The variant is present in GnomAD, with a reported frequency of f = 0.0002226. Functional testing was undertaken at the JKU laboratory. The ACMG criteria applied and the functional testing results can be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at -

Oct 22, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

ALPL-related disorder

Benign:1

Jul 18, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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 provided

Benign:1

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

7.9

DANN

Benign

0.82

DEOGEN2

Benign

0.19

T;T

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.36

.;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.0091

T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

-0.46

N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.17

N;N

REVEL

Uncertain

0.34

Sift

Benign

0.54

T;T

Sift4G

Benign

0.98

T;T

Polyphen

0.0010

B;B

Vest4

0.24

MutPred

0.46

Gain of disorder (P = 0.0692);Gain of disorder (P = 0.0692);

MVP

0.74

MPC

0.36

ClinPred

0.0092

GERP RS

2.5

Varity_R

0.037

gMVP

0.45

Mutation Taster

=100/0

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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