dbSNP rs34810399: ALPL:p.Val461Ile (chr1-21577454-G-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000478.6(ALPL):c.1381G>A(p.Val461Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,611,446 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0079 ( 23 hom., cov: 33)

Exomes 𝑓: 0.00081 ( 13 hom. )

Consequence

ALPL
NM_000478.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.136

Publications

8 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 -17 ACMG points.

PM1

In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000478.6

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 220 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 1.2672 (below the threshold of 3.09). Trascript score misZ: 1.9021 (below the threshold of 3.09). GenCC associations: The gene is linked to adult hypophosphatasia, infantile hypophosphatasia, odontohypophosphatasia, childhood hypophosphatasia, hypophosphatasia, perinatal lethal hypophosphatasia.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055370033).

BP6

Variant 1-21577454-G-A is Benign according to our data. Variant chr1-21577454-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 295552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00792 (1207/152306) while in subpopulation AFR AF = 0.0277 (1151/41566). AF 95% confidence interval is 0.0264. There are 23 homozygotes in GnomAd4. There are 577 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 AD,AR gene

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	UniProt
ALPL	NM_000478.6	MANE Select	c.1381G>A	p.Val461Ile	missense	Exon 12 of 12	NP_000469.3
ALPL	NM_001369803.2		c.1381G>A	p.Val461Ile	missense	Exon 12 of 12	NP_001356732.1	P05186-1
ALPL	NM_001369804.2		c.1381G>A	p.Val461Ile	missense	Exon 12 of 12	NP_001356733.1	P05186-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALPL	ENST00000374840.8	TSL:1 MANE Select	c.1381G>A	p.Val461Ile	missense	Exon 12 of 12	ENSP00000363973.3	P05186-1
ALPL	ENST00000374832.5	TSL:2	c.1381G>A	p.Val461Ile	missense	Exon 12 of 12	ENSP00000363965.1	P05186-1
ALPL	ENST00000879459.1		c.1261G>A	p.Val421Ile	missense	Exon 10 of 10	ENSP00000549518.1

Frequencies

GnomAD3 genomes

AF:

0.00790

AC:

1203

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0277

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00203

AC:

497

AN:

244718

AF XY:

0.00155

show subpopulations

Gnomad AFR exome

AF:

0.0275

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000510

Gnomad NFE exome

AF:

0.0000905

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.000806

AC:

1176

AN:

1459140

Hom.:

Cov.:

AF XY:

0.000684

AC XY:

497

AN XY:

726086

show subpopulations

African (AFR)

AF:

0.0265

AC:

887

AN:

33476

American (AMR)

AF:

0.00143

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.000174

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000197

AC:

AN:

50850

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000818

AC:

AN:

1111916

Other (OTH)

AF:

0.00184

AC:

111

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

168

253

337

421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00792

AC:

1207

AN:

152306

Hom.:

Cov.:

AF XY:

0.00775

AC XY:

577

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0277

AC:

1151

AN:

41566

American (AMR)

AF:

0.00216

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68006

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

113

169

226

282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00289

Hom.:

Bravo

AF:

0.00855

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0225

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00228

AC:

277

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Hypophosphatasia (4)

ALPL-related disorder (1)

not specified (1)

Osteogenesis imperfecta (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Uncertain

0.61

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0055

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.36

PhyloP100

0.14

PrimateAI

Benign

0.34

PROVEAN

Benign

0.070

REVEL

Uncertain

0.29

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.014

Vest4

0.088

MVP

0.87

MPC

0.36

ClinPred

0.0064

GERP RS

3.0

Varity_R

0.030

gMVP

0.60

Mutation Taster

=100/0

polymorphism

(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