1-21570274-C-T

Variant names:

Variant summary

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

-20

BP4_StrongBP6_Very_StrongBA1

The NM_000478.6(ALPL):c.793-31C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,610,114 control chromosomes in the GnomAD database, including 21,467 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1609 hom., cov: 32)

Exomes 𝑓: 0.16 ( 19858 hom. )

Consequence

ALPL
NM_000478.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.10

Publications

26 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=-0.88).

BP6

Variant 1-21570274-C-T is Benign according to our data. Variant chr1-21570274-C-T is described in ClinVar as [Benign]. Clinvar id is 256232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6 link	c.793-31C>T		intron_variant	Intron 7 of 11	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.793-31C>T		intron_variant	Intron 7 of 11	1	NM_000478.6	ENSP00000363973.3		P05186-1

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21420

AN:

152068

Hom.:

1602

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0947

Gnomad AMI

AF:

0.262

Gnomad AMR

AF:

0.148

Gnomad ASJ

AF:

0.224

Gnomad EAS

AF:

0.180

Gnomad SAS

AF:

0.186

Gnomad FIN

AF:

0.106

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.160

Gnomad OTH

AF:

0.163

GnomAD2 exomes

AF:

0.162

AC:

40526

AN:

250202

AF XY:

0.166

show subpopulations

Gnomad AFR exome

AF:

0.0970

Gnomad AMR exome

AF:

0.140

Gnomad ASJ exome

AF:

0.233

Gnomad EAS exome

AF:

0.195

Gnomad FIN exome

AF:

0.108

Gnomad NFE exome

AF:

0.164

Gnomad OTH exome

AF:

0.170

GnomAD4 exome

AF:

0.163

AC:

237261

AN:

1457928

Hom.:

19858

Cov.:

AF XY:

0.164

AC XY:

119111

AN XY:

725528

show subpopulations

African (AFR)

AF:

0.0965

AC:

3223

AN:

33390

American (AMR)

AF:

0.139

AC:

6220

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.220

AC:

5746

AN:

26106

East Asian (EAS)

AF:

0.178

AC:

7077

AN:

39658

South Asian (SAS)

AF:

0.203

AC:

17481

AN:

86116

European-Finnish (FIN)

AF:

0.109

AC:

5788

AN:

53272

Middle Eastern (MID)

AF:

0.205

AC:

1182

AN:

5764

European-Non Finnish (NFE)

AF:

0.163

AC:

180543

AN:

1108734

Other (OTH)

AF:

0.166

AC:

10001

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

10901

21802

32702

43603

54504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6432

12864

19296

25728

32160

<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:

0.141

AC:

21437

AN:

152186

Hom.:

1609

Cov.:

AF XY:

0.139

AC XY:

10348

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0950

AC:

3943

AN:

41520

American (AMR)

AF:

0.148

AC:

2257

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.224

AC:

778

AN:

3470

East Asian (EAS)

AF:

0.180

AC:

930

AN:

5174

South Asian (SAS)

AF:

0.186

AC:

898

AN:

4826

European-Finnish (FIN)

AF:

0.106

AC:

1122

AN:

10596

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.160

AC:

10863

AN:

68002

Other (OTH)

AF:

0.165

AC:

348

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

947

1893

2840

3786

4733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.161

Hom.:

6518

Bravo

AF:

0.145

Asia WGS

AF:

0.178

AC:

621

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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 19, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

-0.88

CADD

Benign

1.8

(source)

DANN

Benign

0.47

PhyloP100

-2.1

PromoterAI

-0.0080

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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