rs1256335

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.473-148G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 997,492 control chromosomes in the GnomAD database, including 317,948 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.80 ( 48679 hom., cov: 27)

Exomes 𝑓: 0.80 ( 269269 hom. )

Consequence

ALPL
NM_000478.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.57

Publications

19 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=-0.91).

BP6

Variant 1-21563893-G-A is Benign according to our data. Variant chr1-21563893-G-A is described in ClinVar as Benign. ClinVar VariationId is 1188974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 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.473-148G>A	intron	N/A	NP_000469.3
ALPL	NM_001369803.2		c.473-148G>A	intron	N/A	NP_001356732.1	P05186-1
ALPL	NM_001369804.2		c.473-148G>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.473-148G>A	intron	N/A	ENSP00000363973.3	P05186-1
ALPL	ENST00000374832.5	TSL:2	c.473-148G>A	intron	N/A	ENSP00000363965.1	P05186-1
ALPL	ENST00000879459.1		c.353-148G>A	intron	N/A	ENSP00000549518.1

Frequencies

GnomAD3 genomes

AF:

0.801

AC:

121136

AN:

151208

Hom.:

48637

Cov.:

show subpopulations

Gnomad AFR

AF:

0.773

Gnomad AMI

AF:

0.848

Gnomad AMR

AF:

0.850

Gnomad ASJ

AF:

0.855

Gnomad EAS

AF:

0.984

Gnomad SAS

AF:

0.812

Gnomad FIN

AF:

0.803

Gnomad MID

AF:

0.816

Gnomad NFE

AF:

0.789

Gnomad OTH

AF:

0.811

GnomAD4 exome

AF:

0.796

AC:

673192

AN:

846166

Hom.:

269269

AF XY:

0.796

AC XY:

343369

AN XY:

431334

show subpopulations

African (AFR)

AF:

0.766

AC:

16480

AN:

21516

American (AMR)

AF:

0.869

AC:

28390

AN:

32680

Ashkenazi Jewish (ASJ)

AF:

0.857

AC:

16295

AN:

19012

East Asian (EAS)

AF:

0.988

AC:

32777

AN:

33176

South Asian (SAS)

AF:

0.795

AC:

48690

AN:

61220

European-Finnish (FIN)

AF:

0.807

AC:

25523

AN:

31644

Middle Eastern (MID)

AF:

0.840

AC:

2486

AN:

2958

European-Non Finnish (NFE)

AF:

0.779

AC:

470557

AN:

604224

Other (OTH)

AF:

0.805

AC:

31994

AN:

39736

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

7064

14128

21192

28256

35320

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8710

17420

26130

34840

43550

<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:

0.801

AC:

121228

AN:

151326

Hom.:

48679

Cov.:

AF XY:

0.807

AC XY:

59589

AN XY:

73860

show subpopulations

African (AFR)

AF:

0.773

AC:

31847

AN:

41184

American (AMR)

AF:

0.850

AC:

12952

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.855

AC:

2967

AN:

3472

East Asian (EAS)

AF:

0.984

AC:

4955

AN:

5034

South Asian (SAS)

AF:

0.811

AC:

3882

AN:

4784

European-Finnish (FIN)

AF:

0.803

AC:

8412

AN:

10480

Middle Eastern (MID)

AF:

0.820

AC:

241

AN:

294

European-Non Finnish (NFE)

AF:

0.789

AC:

53496

AN:

67838

Other (OTH)

AF:

0.812

AC:

1703

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1171

2341

3512

4682

5853

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

870

1740

2610

3480

4350

<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:

0.791

Hom.:

157052

Bravo

AF:

0.801

Asia WGS

AF:

0.874

AC:

3038

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Childhood hypophosphatasia (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.19

(source)

DANN

Benign

0.54

PhyloP100

-1.6

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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