NM_000478.6:c.862+58C>T

Variant names:

• chr1-21570432-C-T
• rs2275375
• NM_000478.6:c.862+58C>T

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.862+58C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,561,994 control chromosomes in the GnomAD database, including 45,066 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5493 hom., cov: 33)
  • Exomes 𝑓: 0.23 (39573 hom.)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.10
• Publications: 7 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 1-21570432-C-T is Benign according to our data. Variant chr1-21570432-C-T is described in ClinVar as Benign. ClinVar VariationId is 1177590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.464 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.862+58C>T		intron	N/A	NP_000469.3
	ALPL	NM_001369803.2		c.862+58C>T		intron	N/A	NP_001356732.1
	ALPL	NM_001369804.2		c.862+58C>T		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.862+58C>T		intron	N/A	ENSP00000363973.3
	ALPL	ENST00000374832.5	TSL:2	c.862+58C>T		intron	N/A	ENSP00000363965.1
	ALPL	ENST00000540617.5	TSL:2	c.697+58C>T		intron	N/A	ENSP00000442672.1

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39605 AN: 151840 Hom.: 5477 Cov.: 33

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.261

GnomAD4 exome AF: 0.228 AC: 320800 AN: 1410036 Hom.: 39573 AF XY: 0.229 AC XY: 160943 AN XY: 703912

African (AFR) AF: 0.321 AC: 10413 AN: 32428

American (AMR) AF: 0.293 AC: 12838 AN: 43782

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 7089 AN: 25722

East Asian (EAS) AF: 0.548 AC: 21516 AN: 39298

South Asian (SAS) AF: 0.289 AC: 24468 AN: 84706

European-Finnish (FIN) AF: 0.295 AC: 15221 AN: 51550

Middle Eastern (MID) AF: 0.245 AC: 1343 AN: 5476

European-Non Finnish (NFE) AF: 0.200 AC: 213607 AN: 1068354

Other (OTH) AF: 0.244 AC: 14305 AN: 58720

GnomAD4 genome AF: 0.261 AC: 39662 AN: 151958 Hom.: 5493 Cov.: 33 AF XY: 0.270 AC XY: 20021 AN XY: 74280

African (AFR) AF: 0.306 AC: 12700 AN: 41436

American (AMR) AF: 0.294 AC: 4490 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 941 AN: 3470

East Asian (EAS) AF: 0.480 AC: 2461 AN: 5130

South Asian (SAS) AF: 0.302 AC: 1457 AN: 4822

European-Finnish (FIN) AF: 0.306 AC: 3237 AN: 10576

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13585 AN: 67932

Other (OTH) AF: 0.264 AC: 557 AN: 2112

Alfa AF: 0.223 Hom.: 1048

Bravo AF: 0.264

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 20, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Infantile hypophosphatasia Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Adult hypophosphatasia Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Childhood hypophosphatasia Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypophosphatasia Benign:1

Aug 29, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

ALPL c.862+58C>T is an intronic variant located in intron 8. This variant is present at high allele frequency in population databases. In conclusion, we classify ALPL c.862+58C>T as a benign variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.45
DANN	Benign	0.45
PhyloP100		-1.1
PromoterAI		-0.025	Neutral
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: rs2275375; hg19: chr1-21896925; COSMIC: COSV66376176; COSMIC: COSV66376176;