chr1-21563893-G-A

Variant names:

• chr1-21563893-G-A
• rs1256335
• NM_000478.6:c.473-148G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000478.6(ALPL):​c.473-148G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 997,492 control chromosomes in the GnomAD database, including 317,948 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (48679 hom., cov: 27)
  • Exomes 𝑓: 0.80 (269269 hom.)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.57
• Publications: 19 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-21563893-G-A is Benign according to our data. Variant chr1-21563893-G-A is described in ClinVar as Benign. ClinVar VariationId is 1188974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

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.473-148G>A		intron	N/A	NP_000469.3
	ALPL	NM_001369803.2		c.473-148G>A		intron	N/A	NP_001356732.1
	ALPL	NM_001369804.2		c.473-148G>A		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.473-148G>A		intron	N/A	ENSP00000363973.3
	ALPL	ENST00000374832.5	TSL:2	c.473-148G>A		intron	N/A	ENSP00000363965.1
	ALPL	ENST00000540617.5	TSL:2	c.308-148G>A		intron	N/A	ENSP00000442672.1

Frequencies

GnomAD3 genomes AF: 0.801 AC: 121136 AN: 151208 Hom.: 48637 Cov.: 27

Gnomad AFR AF: 0.773

Gnomad AMI AF: 0.848

Gnomad AMR AF: 0.850

Gnomad ASJ AF: 0.855

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.812

Gnomad FIN AF: 0.803

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.811

GnomAD4 exome AF: 0.796 AC: 673192 AN: 846166 Hom.: 269269 AF XY: 0.796 AC XY: 343369 AN XY: 431334

African (AFR) AF: 0.766 AC: 16480 AN: 21516

American (AMR) AF: 0.869 AC: 28390 AN: 32680

Ashkenazi Jewish (ASJ) AF: 0.857 AC: 16295 AN: 19012

East Asian (EAS) AF: 0.988 AC: 32777 AN: 33176

South Asian (SAS) AF: 0.795 AC: 48690 AN: 61220

European-Finnish (FIN) AF: 0.807 AC: 25523 AN: 31644

Middle Eastern (MID) AF: 0.840 AC: 2486 AN: 2958

European-Non Finnish (NFE) AF: 0.779 AC: 470557 AN: 604224

Other (OTH) AF: 0.805 AC: 31994 AN: 39736

GnomAD4 genome AF: 0.801 AC: 121228 AN: 151326 Hom.: 48679 Cov.: 27 AF XY: 0.807 AC XY: 59589 AN XY: 73860

African (AFR) AF: 0.773 AC: 31847 AN: 41184

American (AMR) AF: 0.850 AC: 12952 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.855 AC: 2967 AN: 3472

East Asian (EAS) AF: 0.984 AC: 4955 AN: 5034

South Asian (SAS) AF: 0.811 AC: 3882 AN: 4784

European-Finnish (FIN) AF: 0.803 AC: 8412 AN: 10480

Middle Eastern (MID) AF: 0.820 AC: 241 AN: 294

European-Non Finnish (NFE) AF: 0.789 AC: 53496 AN: 67838

Other (OTH) AF: 0.812 AC: 1703 AN: 2098

Alfa AF: 0.791 Hom.: 157052

Bravo AF: 0.801

Asia WGS AF: 0.874 AC: 3038 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Childhood hypophosphatasia Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.19
DANN	Benign	0.54
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs1256335; hg19: chr1-21890386; COSMIC: COSV66379633;