NM_000478.6:c.863-12C>G

Variant names:

• chr1-21573653-C-G
• rs75829132
• NM_000478.6:c.863-12C>G

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.863-12C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,608,524 control chromosomes in the GnomAD database, including 22,663 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3243 hom., cov: 31)
  • Exomes 𝑓: 0.14 (19420 hom.)
• Consequence: ALPL NM_000478.6 intron
• Scores: Splicing: ADA: 0.0001207
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.362
• Publications: 10 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• ALPL-related autosomal dominant hypophosphatasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• childhood hypophosphatasia

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Laboratory for Molecular Medicine, ClinGen
• ALPL-related autosomal recessive hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hypophosphatasia

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• 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 1-21573653-C-G is Benign according to our data. Variant chr1-21573653-C-G is described in ClinVar as Benign. ClinVar VariationId is 256234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.433 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPL	NM_000478.6	MANE Select	c.863-12C>G		intron	N/A	NP_000469.3
	ALPL	NM_001369803.2		c.863-12C>G		intron	N/A	NP_001356732.1	P05186-1
	ALPL	NM_001369804.2		c.863-12C>G		intron	N/A	NP_001356733.1	P05186-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPL	ENST00000374840.8	TSL:1 MANE Select	c.863-12C>G		intron	N/A	ENSP00000363973.3	P05186-1
	ALPL	ENST00000374832.5	TSL:2	c.863-12C>G		intron	N/A	ENSP00000363965.1	P05186-1
	ALPL	ENST00000879459.1		c.743-12C>G		intron	N/A	ENSP00000549518.1

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28577 AN: 151668 Hom.: 3231 Cov.: 31

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.446

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.181 AC: 44850 AN: 247172 AF XY: 0.176

Gnomad AFR exome AF: 0.260

Gnomad AMR exome AF: 0.248

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.433

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.144 AC: 209887 AN: 1456740 Hom.: 19420 Cov.: 33 AF XY: 0.145 AC XY: 104989 AN XY: 724640

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.276 AC: 9199 AN: 33310

American (AMR) AF: 0.245 AC: 10837 AN: 44314

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 3590 AN: 26044

East Asian (EAS) AF: 0.508 AC: 20055 AN: 39462

South Asian (SAS) AF: 0.216 AC: 18505 AN: 85786

European-Finnish (FIN) AF: 0.179 AC: 9482 AN: 53070

Middle Eastern (MID) AF: 0.134 AC: 768 AN: 5722

European-Non Finnish (NFE) AF: 0.115 AC: 127929 AN: 1108796

Other (OTH) AF: 0.158 AC: 9522 AN: 60236

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.189 AC: 28627 AN: 151784 Hom.: 3243 Cov.: 31 AF XY: 0.196 AC XY: 14525 AN XY: 74156

African (AFR) AF: 0.262 AC: 10841 AN: 41356

American (AMR) AF: 0.228 AC: 3482 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 489 AN: 3468

East Asian (EAS) AF: 0.448 AC: 2287 AN: 5106

South Asian (SAS) AF: 0.232 AC: 1112 AN: 4798

European-Finnish (FIN) AF: 0.191 AC: 2010 AN: 10540

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 292

European-Non Finnish (NFE) AF: 0.116 AC: 7868 AN: 67952

Other (OTH) AF: 0.188 AC: 396 AN: 2104

Alfa AF: 0.0929 Hom.: 176

Bravo AF: 0.197

Asia WGS AF: 0.327 AC: 1135 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Hypophosphatasia (2)
-	-	1	Adult hypophosphatasia (1)
-	-	1	Childhood hypophosphatasia (1)
-	-	1	Infantile hypophosphatasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.75
DANN	Benign	0.52
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.072
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: rs75829132; hg19: chr1-21900146; COSMIC: COSV66376541; COSMIC: COSV66376541;