1-21570432-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000478.6(ALPL):c.862+58C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,561,994 control chromosomes in the GnomAD database, including 45,066 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 5493 hom., cov: 33)

Exomes 𝑓: 0.23 ( 39573 hom. )

Consequence

ALPL
NM_000478.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.10

Publications

7 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, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
childhood hypophosphatasia
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, ClinGen, Orphanet
hypophosphatasia
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, G2P
infantile hypophosphatasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 1-21570432-C-T is Benign according to our data. Variant chr1-21570432-C-T is described in ClinVar as Benign. ClinVar VariationId is 1177590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6 link	c.862+58C>T		intron_variant	Intron 8 of 11	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8 link	c.862+58C>T		intron_variant	Intron 8 of 11	1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes

AF:

0.261

AC:

39605

AN:

151840

Hom.:

5477

Cov.:

show subpopulations

Gnomad AFR

AF:

0.306

Gnomad AMI

AF:

0.188

Gnomad AMR

AF:

0.294

Gnomad ASJ

AF:

0.271

Gnomad EAS

AF:

0.477

Gnomad SAS

AF:

0.303

Gnomad FIN

AF:

0.306

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.200

Gnomad OTH

AF:

0.261

GnomAD4 exome

AF:

0.228

AC:

320800

AN:

1410036

Hom.:

39573

AF XY:

0.229

AC XY:

160943

AN XY:

703912

show subpopulations

African (AFR)

AF:

0.321

AC:

10413

AN:

32428

American (AMR)

AF:

0.293

AC:

12838

AN:

43782

Ashkenazi Jewish (ASJ)

AF:

0.276

AC:

7089

AN:

25722

East Asian (EAS)

AF:

0.548

AC:

21516

AN:

39298

South Asian (SAS)

AF:

0.289

AC:

24468

AN:

84706

European-Finnish (FIN)

AF:

0.295

AC:

15221

AN:

51550

Middle Eastern (MID)

AF:

0.245

AC:

1343

AN:

5476

European-Non Finnish (NFE)

AF:

0.200

AC:

213607

AN:

1068354

Other (OTH)

AF:

0.244

AC:

14305

AN:

58720

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

12041

24082

36123

48164

60205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7722

15444

23166

30888

38610

<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:

0.261

AC:

39662

AN:

151958

Hom.:

5493

Cov.:

AF XY:

0.270

AC XY:

20021

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.306

AC:

12700

AN:

41436

American (AMR)

AF:

0.294

AC:

4490

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.271

AC:

941

AN:

3470

East Asian (EAS)

AF:

0.480

AC:

2461

AN:

5130

South Asian (SAS)

AF:

0.302

AC:

1457

AN:

4822

European-Finnish (FIN)

AF:

0.306

AC:

3237

AN:

10576

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.200

AC:

13585

AN:

67932

Other (OTH)

AF:

0.264

AC:

557

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1521

3042

4562

6083

7604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

404

808

1212

1616

2020

<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:

0.223

Hom.:

1048

Bravo

AF:

0.264

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 20, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Infantile hypophosphatasia

Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Adult hypophosphatasia

Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Childhood hypophosphatasia

Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.45

(source)

DANN

Benign

0.45

PhyloP100

-1.1

PromoterAI

-0.025

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over