rs2275376

Variant names:

Your query was ambiguous. Multiple possible variants found:

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+51G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,578,162 control chromosomes in the GnomAD database, including 21,470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 3142 hom., cov: 33)

Exomes 𝑓: 0.14 ( 18328 hom. )

Consequence

ALPL
NM_000478.6 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.34

Publications

11 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
ALPL-related autosomal dominant hypophosphatasia
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
childhood hypophosphatasia
Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Laboratory for Molecular Medicine, ClinGen
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)
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 1-21570425-G-A is Benign according to our data. Variant chr1-21570425-G-A is described in ClinVar as Benign. ClinVar VariationId is 1177589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
ALPL	NM_000478.6	MANE Select	c.862+51G>A	intron	N/A	NP_000469.3
ALPL	NM_001369803.2		c.862+51G>A	intron	N/A	NP_001356732.1	P05186-1
ALPL	NM_001369804.2		c.862+51G>A	intron	N/A	NP_001356733.1	P05186-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ALPL	ENST00000374840.8	TSL:1 MANE Select	c.862+51G>A	intron	N/A	ENSP00000363973.3	P05186-1
ALPL	ENST00000374832.5	TSL:2	c.862+51G>A	intron	N/A	ENSP00000363965.1	P05186-1
ALPL	ENST00000879459.1		c.742+51G>A	intron	N/A	ENSP00000549518.1

Frequencies

GnomAD3 genomes

AF:

0.184

AC:

27964

AN:

151924

Hom.:

3128

Cov.:

show subpopulations

Gnomad AFR

AF:

0.255

Gnomad AMI

AF:

0.118

Gnomad AMR

AF:

0.225

Gnomad ASJ

AF:

0.140

Gnomad EAS

AF:

0.451

Gnomad SAS

AF:

0.234

Gnomad FIN

AF:

0.188

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.111

Gnomad OTH

AF:

0.178

GnomAD2 exomes

AF:

0.183

AC:

44585

AN:

244254

AF XY:

0.177

show subpopulations

Gnomad AFR exome

AF:

0.260

Gnomad AMR exome

AF:

0.249

Gnomad ASJ exome

AF:

0.137

Gnomad EAS exome

AF:

0.439

Gnomad FIN exome

AF:

0.184

Gnomad NFE exome

AF:

0.107

Gnomad OTH exome

AF:

0.155

GnomAD4 exome

AF:

0.141

AC:

200929

AN:

1426120

Hom.:

18328

Cov.:

AF XY:

0.142

AC XY:

100921

AN XY:

711124

show subpopulations

African (AFR)

AF:

0.269

AC:

8802

AN:

32734

American (AMR)

AF:

0.245

AC:

10805

AN:

44120

Ashkenazi Jewish (ASJ)

AF:

0.138

AC:

3569

AN:

25862

East Asian (EAS)

AF:

0.511

AC:

20146

AN:

39440

South Asian (SAS)

AF:

0.217

AC:

18445

AN:

85168

European-Finnish (FIN)

AF:

0.176

AC:

9193

AN:

52120

Middle Eastern (MID)

AF:

0.132

AC:

736

AN:

5584

European-Non Finnish (NFE)

AF:

0.111

AC:

120052

AN:

1081844

Other (OTH)

AF:

0.155

AC:

9181

AN:

59248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

8129

16258

24386

32515

40644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4804

9608

14412

19216

24020

<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:

0.184

AC:

28016

AN:

152042

Hom.:

3142

Cov.:

AF XY:

0.192

AC XY:

14255

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.255

AC:

10591

AN:

41458

American (AMR)

AF:

0.225

AC:

3445

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.140

AC:

487

AN:

3472

East Asian (EAS)

AF:

0.453

AC:

2326

AN:

5134

South Asian (SAS)

AF:

0.233

AC:

1125

AN:

4824

European-Finnish (FIN)

AF:

0.188

AC:

1987

AN:

10584

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.111

AC:

7528

AN:

67972

Other (OTH)

AF:

0.182

AC:

385

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1145

2291

3436

4582

5727

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

292

584

876

1168

1460

<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:

0.145

Hom.:

358

Bravo

AF:

0.192

Asia WGS

AF:

0.327

AC:

1137

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Adult hypophosphatasia (1)

Childhood hypophosphatasia (1)

Hypophosphatasia (1)

Infantile hypophosphatasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.10

(source)

DANN

Benign

0.38

PhyloP100

-2.3

PromoterAI

-0.011

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over