rs786204442

Positions:

chr1-21568246-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PP5_Very_Strong

The ENST00000374840.8(ALPL):c.791A>G(p.Lys264Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000372 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K264N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ALPL
ENST00000374840.8 missense, splice_region

Scores

Splicing: ADA: 0.9990

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 3.69

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in ENST00000374840.8

PP5

Variant 1-21568246-A-G is Pathogenic according to our data. Variant chr1-21568246-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21568246-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALPL	NM_000478.6 linkuse as main transcript	c.791A>G	p.Lys264Arg	missense_variant, splice_region_variant	7/12	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8 linkuse as main transcript	c.791A>G	p.Lys264Arg	missense_variant, splice_region_variant	7/12	1	NM_000478.6	ENSP00000363973	P1	P05186-1
ALPL	ENST00000374832.5 linkuse as main transcript	c.791A>G	p.Lys264Arg	missense_variant, splice_region_variant	7/12	2		ENSP00000363965	P1	P05186-1
ALPL	ENST00000540617.5 linkuse as main transcript	c.626A>G	p.Lys209Arg	missense_variant, splice_region_variant	6/11	2		ENSP00000442672		P05186-3
ALPL	ENST00000539907.5 linkuse as main transcript	c.560A>G	p.Lys187Arg	missense_variant, splice_region_variant	5/10	2		ENSP00000437674		P05186-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Childhood hypophosphatasia;C0268412:Infantile hypophosphatasia;C0268413:Adult hypophosphatasia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 14, 2022

- -

Infantile hypophosphatasia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

literature only

Counsyl

Apr 09, 2014

- -

Adult hypophosphatasia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 03, 2023

- -

Hypophosphatasia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 03, 2020

Variant summary: ALPL c.791A>G (p.Lys264Arg) located in the exonic-splice region of exon 7 results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing leading to a complete skipping of exon 7 (Brun-Heath_2007). The variant was absent in 251140 control chromosomes. c.791A>G has been reported in the literature in at-least one case of a baby girl affected with perinatal Hypophosphatasia (Brun-Heath_2007) as well as adults with this condition and subsequently cited by others (example, Taillandier_2018, Mornet_2008, Silvent_2014). These data indicate that the variant may be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 13, 2023

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change results in skipping of exon 7, but is expected to preserve the integrity of the reading-frame (PMID: 17922851). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 188750). This missense change has been observed in individual(s) with autosomal recessive hypophosphatasia (PMID: 17922851). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs786204442, gnomAD 0.3%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 264 of the ALPL protein (p.Lys264Arg). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

D;.;.;D

Eigen

Benign

-0.090

Eigen_PC

Benign

-0.024

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.79

.;T;T;T

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.43

T;T;T;T

MetaSVM

Uncertain

0.66

MutationAssessor

Benign

1.0

L;.;.;L

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.80

N;N;N;N

REVEL

Uncertain

0.50

Sift

Benign

0.24

T;T;T;T

Sift4G

Benign

0.30

T;T;T;T

Polyphen

0.76

P;.;.;P

Vest4

0.55

MutPred

0.38

Loss of methylation at K264 (P = 0.0653);.;.;Loss of methylation at K264 (P = 0.0653);

MVP

0.96

MPC

0.89

ClinPred

0.80

GERP RS

4.0

Varity_R

0.11

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.32

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over