Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000478.6(ALPL):c.330T>C(p.Ser110Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.941 in 1,613,716 control chromosomes in the GnomAD database, including 714,982 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.93 ( 65398 hom., cov: 34)

Exomes 𝑓: 0.94 ( 649584 hom. )

Consequence

ALPL
NM_000478.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.867

Publications

32 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 1-21563142-T-C is Benign according to our data. Variant chr1-21563142-T-C is described in ClinVar as Benign. ClinVar VariationId is 197678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.867 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 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	HGVSp	Effect	Exon Rank	Protein
ALPL	NM_000478.6	MANE Select	c.330T>C	p.Ser110Ser	synonymous	Exon 5 of 12	NP_000469.3
ALPL	NM_001369803.2		c.330T>C	p.Ser110Ser	synonymous	Exon 5 of 12	NP_001356732.1
ALPL	NM_001369804.2		c.330T>C	p.Ser110Ser	synonymous	Exon 5 of 12	NP_001356733.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALPL	ENST00000374840.8	TSL:1 MANE Select	c.330T>C	p.Ser110Ser	synonymous	Exon 5 of 12	ENSP00000363973.3
ALPL	ENST00000374832.5	TSL:2	c.330T>C	p.Ser110Ser	synonymous	Exon 5 of 12	ENSP00000363965.1
ALPL	ENST00000540617.5	TSL:2	c.165T>C	p.Ser55Ser	synonymous	Exon 4 of 11	ENSP00000442672.1

Frequencies

GnomAD3 genomes

AF:

0.926

AC:

140906

AN:

152174

Hom.:

65340

Cov.:

show subpopulations

Gnomad AFR

AF:

0.867

Gnomad AMI

AF:

0.989

Gnomad AMR

AF:

0.953

Gnomad ASJ

AF:

0.977

Gnomad EAS

AF:

0.987

Gnomad SAS

AF:

0.956

Gnomad FIN

AF:

0.937

Gnomad MID

AF:

0.927

Gnomad NFE

AF:

0.944

Gnomad OTH

AF:

0.932

GnomAD2 exomes

AF:

0.947

AC:

237694

AN:

250932

AF XY:

0.948

show subpopulations

Gnomad AFR exome

AF:

0.865

Gnomad AMR exome

AF:

0.968

Gnomad ASJ exome

AF:

0.978

Gnomad EAS exome

AF:

0.986

Gnomad FIN exome

AF:

0.938

Gnomad NFE exome

AF:

0.943

Gnomad OTH exome

AF:

0.951

GnomAD4 exome

AF:

0.943

AC:

1377566

AN:

1461424

Hom.:

649584

Cov.:

AF XY:

0.943

AC XY:

685845

AN XY:

727046

show subpopulations

African (AFR)

AF:

0.860

AC:

28792

AN:

33480

American (AMR)

AF:

0.965

AC:

43154

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.978

AC:

25562

AN:

26134

East Asian (EAS)

AF:

0.990

AC:

39284

AN:

39700

South Asian (SAS)

AF:

0.955

AC:

82362

AN:

86258

European-Finnish (FIN)

AF:

0.937

AC:

49634

AN:

52984

Middle Eastern (MID)

AF:

0.948

AC:

5467

AN:

5768

European-Non Finnish (NFE)

AF:

0.941

AC:

1046415

AN:

1111988

Other (OTH)

AF:

0.942

AC:

56896

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

5336

10672

16008

21344

26680

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21590

43180

64770

86360

107950

<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:

0.926

AC:

141023

AN:

152292

Hom.:

65398

Cov.:

AF XY:

0.929

AC XY:

69138

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.867

AC:

36031

AN:

41560

American (AMR)

AF:

0.953

AC:

14579

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.977

AC:

3392

AN:

3472

East Asian (EAS)

AF:

0.988

AC:

5106

AN:

5170

South Asian (SAS)

AF:

0.956

AC:

4615

AN:

4828

European-Finnish (FIN)

AF:

0.937

AC:

9950

AN:

10622

Middle Eastern (MID)

AF:

0.929

AC:

273

AN:

294

European-Non Finnish (NFE)

AF:

0.944

AC:

64204

AN:

68020

Other (OTH)

AF:

0.933

AC:

1971

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

541

1082

1624

2165

2706

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<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:

0.939

Hom.:

136647

Bravo

AF:

0.921

Asia WGS

AF:

0.970

AC:

3372

AN:

3478

EpiCase

AF:

0.946

EpiControl

AF:

0.941

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Hypophosphatasia (3)

not provided (2)

Adult hypophosphatasia (1)

Childhood hypophosphatasia (1)

Infantile hypophosphatasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

1.2

(source)

DANN

Benign

0.32

PhyloP100

-0.87

Mutation Taster

=96/4

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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rs1780316

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over