1-21577613-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_000478.6(ALPL):c.1540G>T(p.Ala514Ser) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A514V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ALPL
NM_000478.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0130

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

adult hypophosphatasia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
ALPL-related autosomal dominant hypophosphatasia
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
childhood hypophosphatasia
Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Orphanet
ALPL-related autosomal recessive hypophosphatasia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hypophosphatasia
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, G2P
infantile hypophosphatasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
odontohypophosphatasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
perinatal lethal hypophosphatasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ALPL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 adult hypophosphatasia, infantile hypophosphatasia, odontohypophosphatasia, childhood hypophosphatasia, hypophosphatasia, perinatal lethal hypophosphatasia.

BP4

Computational evidence support a benign effect (MetaRNN=0.08198497).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000478.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALPL	NM_000478.6	MANE Select	c.1540G>T	p.Ala514Ser	missense	Exon 12 of 12	NP_000469.3
ALPL	NM_001369803.2		c.1540G>T	p.Ala514Ser	missense	Exon 12 of 12	NP_001356732.1	P05186-1
ALPL	NM_001369804.2		c.1540G>T	p.Ala514Ser	missense	Exon 12 of 12	NP_001356733.1	P05186-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALPL	ENST00000374840.8	TSL:1 MANE Select	c.1540G>T	p.Ala514Ser	missense	Exon 12 of 12	ENSP00000363973.3	P05186-1
ALPL	ENST00000374832.5	TSL:2	c.1540G>T	p.Ala514Ser	missense	Exon 12 of 12	ENSP00000363965.1	P05186-1
ALPL	ENST00000879459.1		c.1420G>T	p.Ala474Ser	missense	Exon 10 of 10	ENSP00000549518.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1447508

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720664

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.00

AC:

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39636

South Asian (SAS)

AF:

0.00

AC:

AN:

86086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111468

Other (OTH)

AF:

0.00

AC:

AN:

60258

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Childhood hypophosphatasia;C0268412:Infantile hypophosphatasia;C0268413:Adult hypophosphatasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.0066

BayesDel_noAF

Benign

-0.25

CADD

Benign

1.0

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.23

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.37

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.082

MetaSVM

Uncertain

-0.17

MutationAssessor

Benign

0.0

PhyloP100

0.013

PrimateAI

Benign

0.33

PROVEAN

Benign

0.14

REVEL

Benign

0.26

Sift

Benign

0.60

Sift4G

Benign

0.79

Polyphen

0.020

Vest4

0.15

MutPred

0.37

Loss of helix (P = 0.0304)

MVP

0.82

MPC

0.37

ClinPred

0.025

GERP RS

3.0

Varity_R

0.044

gMVP

0.65

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over