rs1130335

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001632.5(ALPP):c.74C>T(p.Pro25Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.081 in 1,613,864 control chromosomes in the GnomAD database, including 6,187 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.070 ( 485 hom., cov: 32)

Exomes 𝑓: 0.082 ( 5702 hom. )

Consequence

ALPP
NM_001632.5 missense, splice_region

Scores

Splicing: ADA: 0.8676

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.71

Publications

15 publications found

Variant links:

Genes affected

ALPP (HGNC:439): (alkaline phosphatase, placental) The protein encoded by this gene is an alkaline phosphatase, a metalloenzyme that catalyzes the hydrolysis of phosphoric acid monoesters. It belongs to a multigene family composed of four alkaline phosphatase isoenzymes. The enzyme functions as a homodimer and has a catalytic site containing one magnesium and two zinc ions, which are required for its enzymatic function. One of the main sources of this enzyme is the liver, and thus, it's one of several indicators of liver injury in different clinical conditions. In pregnant women, this protein is primarily expressed in placental and endometrial tissue, however, strong ectopic expression has been detected in ovarian adenocarcinoma, serous cystadenocarcinoma, and other ovarian cancer cells. [provided by RefSeq, Aug 2020]

ALPP links:

ECEL1P2 (HGNC:):

ECEL1P2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017961562).

BP6

Variant 2-232378876-C-T is Benign according to our data. Variant chr2-232378876-C-T is described in ClinVar as Benign. ClinVar VariationId is 13661.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPP	NM_001632.5 link	c.74C>T	p.Pro25Leu	missense_variant, splice_region_variant	Exon 1 of 11	ENST00000392027.3	NP_001623.3	P05187B2R7C7
LOC124906123	XR_007088121.1 link	n.88+69G>A		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ALPP	ENST00000392027.3 link	c.74C>T	p.Pro25Leu	missense_variant, splice_region_variant	Exon 1 of 11	1	NM_001632.5	ENSP00000375881.2	P05187
ALPP	ENST00000474529.1 link	n.153C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 4	2
ECEL1P2	ENST00000715297.1 link	n.812+69G>A		intron_variant	Intron 4 of 6

Frequencies

GnomAD3 genomes

AF:

0.0702

AC:

10670

AN:

151936

Hom.:

485

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0385

Gnomad AMI

AF:

0.0593

Gnomad AMR

AF:

0.0564

Gnomad ASJ

AF:

0.0525

Gnomad EAS

AF:

0.224

Gnomad SAS

AF:

0.0720

Gnomad FIN

AF:

0.0587

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0835

Gnomad OTH

AF:

0.0740

GnomAD2 exomes

AF:

0.0801

AC:

20113

AN:

251184

AF XY:

0.0802

show subpopulations

Gnomad AFR exome

AF:

0.0393

Gnomad AMR exome

AF:

0.0377

Gnomad ASJ exome

AF:

0.0487

Gnomad EAS exome

AF:

0.222

Gnomad FIN exome

AF:

0.0626

Gnomad NFE exome

AF:

0.0849

Gnomad OTH exome

AF:

0.0829

GnomAD4 exome

AF:

0.0822

AC:

120106

AN:

1461810

Hom.:

5702

Cov.:

AF XY:

0.0818

AC XY:

59521

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.0358

AC:

1199

AN:

33478

American (AMR)

AF:

0.0402

AC:

1799

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0511

AC:

1335

AN:

26132

East Asian (EAS)

AF:

0.232

AC:

9197

AN:

39698

South Asian (SAS)

AF:

0.0664

AC:

5723

AN:

86240

European-Finnish (FIN)

AF:

0.0663

AC:

3540

AN:

53404

Middle Eastern (MID)

AF:

0.0552

AC:

318

AN:

5764

European-Non Finnish (NFE)

AF:

0.0828

AC:

92066

AN:

1111982

Other (OTH)

AF:

0.0816

AC:

4929

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

6978

13955

20933

27910

34888

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3384

6768

10152

13536

16920

<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:

0.0702

AC:

10669

AN:

152054

Hom.:

485

Cov.:

AF XY:

0.0692

AC XY:

5146

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.0385

AC:

1598

AN:

41464

American (AMR)

AF:

0.0563

AC:

860

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0525

AC:

182

AN:

3466

East Asian (EAS)

AF:

0.225

AC:

1160

AN:

5162

South Asian (SAS)

AF:

0.0714

AC:

343

AN:

4804

European-Finnish (FIN)

AF:

0.0587

AC:

622

AN:

10596

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0835

AC:

5675

AN:

67978

Other (OTH)

AF:

0.0737

AC:

155

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

459

918

1377

1836

2295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<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:

0.0804

Hom.:

1370

Bravo

AF:

0.0682

TwinsUK

AF:

0.0809

AC:

300

ALSPAC

AF:

0.0843

AC:

325

ESP6500AA

AF:

0.0415

AC:

183

ESP6500EA

AF:

0.0812

AC:

698

ExAC

AF:

0.0819

AC:

9941

Asia WGS

AF:

0.114

AC:

398

AN:

3478

EpiCase

AF:

0.0809

EpiControl

AF:

0.0828

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ALKALINE PHOSPHATASE, PLACENTAL, ALLELE-3 POLYMORPHISM

Benign:1

Aug 01, 1986

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Benign

-0.0024

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

PhyloP100

1.7

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.1

REVEL

Uncertain

0.33

Sift

Uncertain

0.027

Sift4G

Uncertain

0.043

Polyphen

1.0

Vest4

0.084

MPC

0.44

ClinPred

0.052

GERP RS

1.8

PromoterAI

-0.037

Neutral

(source)

Varity_R

0.42

gMVP

0.59

Mutation Taster

=91/9

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.87

dbscSNV1_RF

Benign

0.64

SpliceAI score (max)

0.010

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