rs1553413155

Variant names:

• chr1-21568105-T-CTAA
• rs1553413155
• NM_000478.6:c.650delTinsCTAA

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM4_Supporting PP2 PP3 PP5_Very_Strong

The NM_000478.6(ALPL):​c.650delTinsCTAA​(p.Val217delinsAlaLys) variant causes a missense, disruptive inframe insertion, 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V217A) has been classified as Uncertain significance.

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

ACMG classification

Our verdict: Pathogenic. The variant received 15 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
• 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.
• 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.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 555056.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.650delTinsCTAA	p.Val217delinsAlaLys	missense disruptive_inframe_insertion splice_region	Exon 7 of 12	NP_000469.3
	ALPL	NM_001369803.2		c.650delTinsCTAA	p.Val217delinsAlaLys	missense disruptive_inframe_insertion splice_region	Exon 7 of 12	NP_001356732.1	P05186-1
	ALPL	NM_001369804.2		c.650delTinsCTAA	p.Val217delinsAlaLys	missense disruptive_inframe_insertion splice_region	Exon 7 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.650delTinsCTAA	p.Val217delinsAlaLys	missense disruptive_inframe_insertion splice_region	Exon 7 of 12	ENSP00000363973.3	P05186-1
	ALPL	ENST00000374832.5	TSL:2	c.650delTinsCTAA	p.Val217delinsAlaLys	missense disruptive_inframe_insertion splice_region	Exon 7 of 12	ENSP00000363965.1	P05186-1
	ALPL	ENST00000879459.1		c.530delTinsCTAA	p.Val177delinsAlaLys	missense disruptive_inframe_insertion splice_region	Exon 5 of 10	ENSP00000549518.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=1/199	disease causing

Splicing

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

Other links and lift over

dbSNP: rs1553413155; hg19: chr1-21894598;