NM_000478.6:c.472+11_472+12delGG

Variant names:

• chr1-21563291-CGG-C
• rs35423948
• NM_000478.6:c.472+11_472+12delGG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000478.6(ALPL):​c.472+11_472+12delGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.749
• Publications: 2 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: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
• childhood hypophosphatasia

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, ClinGen, Orphanet
• hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, G2P
• infantile hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia
• odontohypophosphatasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• perinatal lethal hypophosphatasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPL	NM_000478.6	MANE Select	c.472+11_472+12delGG		intron	N/A	NP_000469.3
	ALPL	NM_001369803.2		c.472+11_472+12delGG		intron	N/A	NP_001356732.1
	ALPL	NM_001369804.2		c.472+11_472+12delGG		intron	N/A	NP_001356733.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPL	ENST00000374840.8	TSL:1 MANE Select	c.472+8_472+9delGG		splice_region intron	N/A	ENSP00000363973.3
	ALPL	ENST00000374832.5	TSL:2	c.472+8_472+9delGG		splice_region intron	N/A	ENSP00000363965.1
	ALPL	ENST00000540617.5	TSL:2	c.307+8_307+9delGG		splice_region intron	N/A	ENSP00000442672.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455214 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 723042

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25744

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.00 AC: 0 AN: 85690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5590

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107774

Other (OTH) AF: 0.00 AC: 0 AN: 60104

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs35423948; hg19: chr1-21889784;