1-21570425-G-A

Variant names:

• chr1-21570425-G-A
• rs2275376
• NM_000478.6:c.862+51G>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.862+51G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,578,162 control chromosomes in the GnomAD database, including 21,470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3142 hom., cov: 33)
  • Exomes 𝑓: 0.14 (18328 hom.)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.34
• Publications: 11 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=-0.88).
• BP6: Variant 1-21570425-G-A is Benign according to our data. Variant chr1-21570425-G-A is described in ClinVar as Benign. ClinVar VariationId is 1177589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6	c.862+51G>A		intron_variant	Intron 8 of 11	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8	c.862+51G>A		intron_variant	Intron 8 of 11	1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27964 AN: 151924 Hom.: 3128 Cov.: 33

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.178

GnomAD2 exomes AF: 0.183 AC: 44585 AN: 244254 AF XY: 0.177

Gnomad AFR exome AF: 0.260

Gnomad AMR exome AF: 0.249

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.439

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.141 AC: 200929 AN: 1426120 Hom.: 18328 Cov.: 28 AF XY: 0.142 AC XY: 100921 AN XY: 711124

African (AFR) AF: 0.269 AC: 8802 AN: 32734

American (AMR) AF: 0.245 AC: 10805 AN: 44120

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 3569 AN: 25862

East Asian (EAS) AF: 0.511 AC: 20146 AN: 39440

South Asian (SAS) AF: 0.217 AC: 18445 AN: 85168

European-Finnish (FIN) AF: 0.176 AC: 9193 AN: 52120

Middle Eastern (MID) AF: 0.132 AC: 736 AN: 5584

European-Non Finnish (NFE) AF: 0.111 AC: 120052 AN: 1081844

Other (OTH) AF: 0.155 AC: 9181 AN: 59248

GnomAD4 genome AF: 0.184 AC: 28016 AN: 152042 Hom.: 3142 Cov.: 33 AF XY: 0.192 AC XY: 14255 AN XY: 74326

African (AFR) AF: 0.255 AC: 10591 AN: 41458

American (AMR) AF: 0.225 AC: 3445 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 487 AN: 3472

East Asian (EAS) AF: 0.453 AC: 2326 AN: 5134

South Asian (SAS) AF: 0.233 AC: 1125 AN: 4824

European-Finnish (FIN) AF: 0.188 AC: 1987 AN: 10584

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7528 AN: 67972

Other (OTH) AF: 0.182 AC: 385 AN: 2112

Alfa AF: 0.145 Hom.: 358

Bravo AF: 0.192

Asia WGS AF: 0.327 AC: 1137 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 20, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.10
DANN	Benign	0.38
PhyloP100		-2.3
PromoterAI		-0.011	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: rs2275376; hg19: chr1-21896918; COSMIC: COSV66376174; COSMIC: COSV66376174;