rs1553413155

Positions:

• chr1-21568104-GT-GCTAA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM4_Supporting PP3 PP5_Very_Strong

The NM_000478.6(ALPL):​c.650delinsCTAA​(p.Val217delinsAlaLys) variant causes a protein altering, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALPL NM_000478.6 protein_altering, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 7.62

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000478.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000478.6. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 1-21568105-T-CTAA is Pathogenic according to our data. Variant chr1-21568105-T-CTAA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6	c.650delinsCTAA	p.Val217delinsAlaLys	protein_altering_variant, splice_region_variant	7/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.650delinsCTAA	p.Val217delinsAlaLys	protein_altering_variant, splice_region_variant	7/12	1	NM_000478.6	P1
ALPL	ENST00000374832.5	c.650delinsCTAA	p.Val217delinsAlaLys	protein_altering_variant, splice_region_variant	7/12	2		P1
ALPL	ENST00000540617.5	c.485delinsCTAA	p.Val162delinsAlaLys	protein_altering_variant, splice_region_variant	6/11	2
ALPL	ENST00000539907.5	c.419delinsCTAA	p.Val140delinsAlaLys	protein_altering_variant, splice_region_variant	5/10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2022	In-frame deletion of 1 amino acid and insertion of 2 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34712267, 21638016) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This variant, c.650delinsCTAA, is a complex sequence change that results in the deletion of 1 and insertion of 2 amino acid(s) in the ALPL protein (p.Val217delinsAlaLys). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individual(s) with autosomal recessive hypophosphatasia (PMID: 21638016, 34712267, 36427976). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. -

Hypophosphatasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Nov 13, 2023

Variant summary: ALPL c.650delinsCTAA (p.Val217delinsAlaLys) results in an in-frame deletion-insertion that is predicted to delete Val amino acid and replace with Ala and Lys amino acids. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251464 control chromosomes (gnomAD). c.650delinsCTAA has been reported in the literature in bi-allelic individuals affected with autosomal recessive Hypophosphatasia (examples: Chang_2012, Zhang_2021,You_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21638016, 34712267, 31687651, 36427976). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Infantile hypophosphatasia Uncertain:1

Uncertain significance, flagged submission

clinical testing

Counsyl

Nov 17, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553413155; hg19: chr1-21894598;