chr1-21575943-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000478.6(ALPL):c.1189+19G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.029 in 1,614,054 control chromosomes in the GnomAD database, including 800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 63 hom., cov: 32)

Exomes 𝑓: 0.030 ( 737 hom. )

Consequence

ALPL
NM_000478.6 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.364

Publications

2 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=-0.83).

BP6

Variant 1-21575943-G-T is Benign according to our data. Variant chr1-21575943-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.021 (3204/152294) while in subpopulation NFE AF = 0.0348 (2369/68022). AF 95% confidence interval is 0.0337. There are 63 homozygotes in GnomAd4. There are 1459 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 63 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6 link	c.1189+19G>T		intron_variant	Intron 10 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.1189+19G>T		intron_variant	Intron 10 of 11	1	NM_000478.6	ENSP00000363973.3		P05186-1

Frequencies

GnomAD3 genomes

AF:

0.0211

AC:

3204

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00456

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.00883

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00498

Gnomad FIN

AF:

0.0261

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0348

Gnomad OTH

AF:

0.0196

GnomAD2 exomes

AF:

0.0218

AC:

5466

AN:

251306

AF XY:

0.0220

show subpopulations

Gnomad AFR exome

AF:

0.00535

Gnomad AMR exome

AF:

0.00841

Gnomad ASJ exome

AF:

0.0154

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0300

Gnomad NFE exome

AF:

0.0345

Gnomad OTH exome

AF:

0.0215

GnomAD4 exome

AF:

0.0298

AC:

43591

AN:

1461760

Hom.:

737

Cov.:

AF XY:

0.0291

AC XY:

21177

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.00397

AC:

133

AN:

33478

American (AMR)

AF:

0.00908

AC:

406

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0155

AC:

406

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00711

AC:

613

AN:

86242

European-Finnish (FIN)

AF:

0.0313

AC:

1671

AN:

53418

Middle Eastern (MID)

AF:

0.00728

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0350

AC:

38875

AN:

1111908

Other (OTH)

AF:

0.0239

AC:

1444

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

2278

4556

6834

9112

11390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1420

2840

4260

5680

7100

<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:

0.0210

AC:

3204

AN:

152294

Hom.:

Cov.:

AF XY:

0.0196

AC XY:

1459

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00455

AC:

189

AN:

41560

American (AMR)

AF:

0.00876

AC:

134

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00519

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0261

AC:

277

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0348

AC:

2369

AN:

68022

Other (OTH)

AF:

0.0194

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

162

323

485

646

808

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0290

Hom.:

Bravo

AF:

0.0201

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 09, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Infantile hypophosphatasia

Benign:1

Dec 19, 2017

Counsyl

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.3

(source)

DANN

Benign

0.53

PhyloP100

-0.36

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