1-21554102-ACTGGCCATTGG-GTGT

Variant names:

• chr1-21554102-ACTGGCCATTGG-GTGT
• rs1644366950
• NM_000478.6:c.21_32delACTGGCCATTGGinsGTGT

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PM2 PP2 PP5_Moderate

The NM_000478.6(ALPL):​c.21_32delACTGGCCATTGGinsGTGT​(p.Leu8CysfsTer6) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ALPL NM_000478.6 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.33
• Publications: 0 publications found

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

ENSG00000289715 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 567 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 1-21554102-ACTGGCCATTGG-GTGT is Pathogenic according to our data. Variant chr1-21554102-ACTGGCCATTGG-GTGT is described in ClinVar as Pathogenic. ClinVar VariationId is 966449.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPL	NM_000478.6	MANE Select	c.21_32delACTGGCCATTGGinsGTGT	p.Leu8CysfsTer6	frameshift missense	Exon 2 of 12	NP_000469.3
	ALPL	NM_001369803.2		c.21_32delACTGGCCATTGGinsGTGT	p.Leu8CysfsTer6	frameshift missense	Exon 2 of 12	NP_001356732.1	P05186-1
	ALPL	NM_001369804.2		c.21_32delACTGGCCATTGGinsGTGT	p.Leu8CysfsTer6	frameshift missense	Exon 2 of 12	NP_001356733.1	P05186-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPL	ENST00000374840.8	TSL:1 MANE Select	c.21_32delACTGGCCATTGGinsGTGT	p.Leu8CysfsTer6	frameshift missense	Exon 2 of 12	ENSP00000363973.3	P05186-1
	ALPL	ENST00000374832.5	TSL:2	c.21_32delACTGGCCATTGGinsGTGT	p.Leu8CysfsTer6	frameshift missense	Exon 2 of 12	ENSP00000363965.1	P05186-1
	ALPL	ENST00000879459.1		c.21_32delACTGGCCATTGGinsGTGT	p.Leu8CysfsTer6	frameshift missense	Exon 1 of 10	ENSP00000549518.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3

Splicing

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

Other links and lift over

dbSNP: rs1644366950; hg19: chr1-21880595;