chr1-21563212-AC-CA

Variant names:

• chr1-21563212-AC-CA
• rs786204530
• NM_000478.6:c.400_401delACinsCA

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM5 PP2 PP5_Very_Strong

The NM_000478.6(ALPL):​c.400_401delACinsCA​(p.Thr134His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.0000518 in 13 alleles, including 0 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000329063: Published functional studies demonstrate the variant abolishes enzyme activity (PMID:25736332)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T134N) has been classified as Likely pathogenic.

• Frequency: GnomAD MNV: 𝑓 0.000052 Genomes: not found (cov: 33)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 6.64
• Publications: 3 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

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000329063: Published functional studies demonstrate the variant abolishes enzyme activity (PMID: 25736332); SCV005077269: The variant results in 10%-<30% of normal enzymatic activity (del Angel_2020). PMID: 32160374; SCV006334841: At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:32160374;25736332).
• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000478.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-21563213-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4086804.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 ALPL-related autosomal dominant hypophosphatasia, ALPL-related autosomal recessive hypophosphatasia, infantile hypophosphatasia, hypophosphatasia, adult hypophosphatasia, odontohypophosphatasia, childhood hypophosphatasia, perinatal lethal hypophosphatasia.
• PP5: Variant 1-21563212-AC-CA is Pathogenic according to our data. Variant chr1-21563212-AC-CA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 188877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.400_401delACinsCA	p.Thr134His	missense	N/A	NP_000469.3
	ALPL	NM_001369803.2		c.400_401delACinsCA	p.Thr134His	missense	N/A	NP_001356732.1	P05186-1
	ALPL	NM_001369804.2		c.400_401delACinsCA	p.Thr134His	missense	N/A	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.400_401delACinsCA	p.Thr134His	missense	N/A	ENSP00000363973.3	P05186-1
	ALPL	ENST00000374832.5	TSL:2	c.400_401delACinsCA	p.Thr134His	missense	N/A	ENSP00000363965.1	P05186-1
	ALPL	ENST00000879459.1		c.280_281delACinsCA	p.Thr94His	missense	N/A	ENSP00000549518.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

GnomAD MNV AF: 0.0000518 AC: 13 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Hypophosphatasia (2)
1	-	-	Adult hypophosphatasia (1)
1	-	-	Childhood hypophosphatasia;C0268412:Infantile hypophosphatasia;C0268413:Adult hypophosphatasia (1)
1	-	-	Infantile hypophosphatasia (1)
-	-	-	Hypophosphatemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.6
Mutation Taster		=0/100	disease causing

Splicing

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

Other links and lift over

dbSNP: rs786204530; hg19: chr1-21889705;