1-21563225-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PP5_ModerateBP4

The NM_000478.6(ALPL):​c.413G>C​(p.Arg138Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R138Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

ALPL
NM_000478.6 missense

Scores

1
8
10

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.85
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000478.6
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-21563225-G-C is Pathogenic according to our data. Variant chr1-21563225-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2676516.Status of the report is criteria_provided_single_submitter, 1 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.35796678). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALPLNM_000478.6 linkc.413G>C p.Arg138Pro missense_variant Exon 5 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.413G>C p.Arg138Pro missense_variant Exon 5 of 12 1 NM_000478.6 ENSP00000363973.3 P05186-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
37
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Adult hypophosphatasia Pathogenic:1
Aug 24, 2023
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.84
BayesDel_addAF
Uncertain
0.092
D
BayesDel_noAF
Benign
-0.11
CADD
Benign
17
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.78
D;.;.;D
Eigen
Benign
-0.59
Eigen_PC
Benign
-0.51
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.88
.;D;D;D
M_CAP
Uncertain
0.22
D
MetaRNN
Benign
0.36
T;T;T;T
MetaSVM
Uncertain
-0.041
T
MutationAssessor
Benign
-0.85
N;.;.;N
PrimateAI
Benign
0.22
T
PROVEAN
Benign
-1.7
N;N;N;N
REVEL
Uncertain
0.46
Sift
Benign
0.047
D;T;D;D
Sift4G
Benign
0.075
T;T;T;T
Polyphen
0.81
P;.;.;P
Vest4
0.30
MutPred
0.53
Loss of MoRF binding (P = 0.0312);.;.;Loss of MoRF binding (P = 0.0312);
MVP
0.86
MPC
1.1
ClinPred
0.64
D
GERP RS
1.0
Varity_R
0.29
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-21889718; API