1-21554125-C-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6_Very_StrongBS2_Supporting

The NM_000478.6(ALPL):ā€‹c.44C>Gā€‹(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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…). Synonymous variant affecting the same amino acid position (i.e. T15T) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.00011 ( 0 hom., cov: 31)
Exomes š‘“: 0.00023 ( 4 hom. )

Consequence

ALPL
NM_000478.6 missense

Scores

2
17

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 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
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
ALPLNM_000478.6 linkc.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
ALPLENST00000374840.8 linkc.44C>G p.Thr15Ser missense_variant Exon 2 of 12 1 NM_000478.6 ENSP00000363973.3 P05186-1

Frequencies

GnomAD3 genomes
AF:
0.000113
AC:
17
AN:
150478
Hom.:
0
Cov.:
31
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
GnomAD3 exomes
AF:
0.000469
AC:
118
AN:
251480
Hom.:
2
AF XY:
0.000684
AC XY:
93
AN XY:
135916
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 SAS exome
AF:
0.00379
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.:
4
Cov.:
33
AF XY:
0.000323
AC XY:
231
AN XY:
716070
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00369
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000100
Gnomad4 OTH exome
AF:
0.000153
GnomAD4 genome
AF:
0.000113
AC:
17
AN:
150594
Hom.:
0
Cov.:
31
AF XY:
0.000190
AC XY:
14
AN XY:
73612
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000661
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00278
Gnomad4 FIN
AF:
0.0000970
Gnomad4 NFE
AF:
0.0000296
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.000576
AC:
70
Asia WGS
AF:
0.00231
AC:
8
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
Likely benign, criteria provided, single submitterclinical testing;in vitroJKU Lab, Dept of Paediatrics, Johannes Kepler UniversityOct 08, 2024The 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 -
Benign, no assertion criteria providedclinical testingNatera, Inc.Oct 22, 2019- -
ALPL-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 18, 2022This 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
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 03, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Benign
-0.40
T
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
D
LIST_S2
Benign
0.36
.;T
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.0091
T;T
MetaSVM
Benign
-0.53
T
MutationAssessor
Benign
-0.46
N;N
PrimateAI
Benign
0.37
T
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
T
GERP RS
2.5
Varity_R
0.037
gMVP
0.45

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.

Other links and lift over

dbSNP: rs150849772; hg19: chr1-21880618; API