1-21568111-TG-TGG

Variant names:

• chr1-21568111-T-TG
• rs769948289
• NM_000478.6:c.662dupG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000478.6(ALPL):​c.662dupG​(p.Gly222TrpfsTer10) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALPL NM_000478.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.19

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-21568111-T-TG is Pathogenic according to our data. Variant chr1-21568111-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6	c.662dupG	p.Gly222TrpfsTer10	frameshift_variant	Exon 7 of 12	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8	c.662dupG	p.Gly222TrpfsTer10	frameshift_variant	Exon 7 of 12	1	NM_000478.6	ENSP00000363973.3
ALPL	ENST00000374832.5	c.662dupG	p.Gly222TrpfsTer10	frameshift_variant	Exon 7 of 12	2		ENSP00000363965.1
ALPL	ENST00000540617.5	c.497dupG	p.Gly167TrpfsTer10	frameshift_variant	Exon 6 of 11	2		ENSP00000442672.1
ALPL	ENST00000539907.5	c.431dupG	p.Gly145TrpfsTer10	frameshift_variant	Exon 5 of 10	2		ENSP00000437674.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461826 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

May 07, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ALPL are known to be pathogenic (PMID: 3174660, 10679946, 19500388). This variant has been observed in a fetus with clinical features of hypophosphatasia (PMID: 18925618). This variant is also known as 662insG in the literature. ClinVar contains an entry for this variant (Variation ID: 370379). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gly222Trpfs*10) in the ALPL gene. It is expected to result in an absent or disrupted protein product. -

Jul 17, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Reported with a second ALPL variant, phase unknown, in a fetus with hypophosphatasia (Simon-Bouy et al., 2008); This variant is associated with the following publications: (PMID: 10737975, 27397505, 18925618) -

Infantile hypophosphatasia Pathogenic:1

Jan 28, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Adult hypophosphatasia Pathogenic:1

Nov 16, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs769948289; hg19: chr1-21894604;