chr1-21567814-T-C

Variant names:

• chr1-21567814-T-C
• rs10917008
• NM_000478.6:c.649-290T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000478.6(ALPL):​c.649-290T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 152,102 control chromosomes in the GnomAD database, including 6,556 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.29 (6556 hom., cov: 32)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.340
• 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: 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-21567814-T-C is Benign according to our data. Variant chr1-21567814-T-C is described in ClinVar as Benign. ClinVar VariationId is 1243260.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.37 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.649-290T>C		intron	N/A	NP_000469.3
	ALPL	NM_001369803.2		c.649-290T>C		intron	N/A	NP_001356732.1
	ALPL	NM_001369804.2		c.649-290T>C		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.649-290T>C		intron	N/A	ENSP00000363973.3
	ALPL	ENST00000374832.5	TSL:2	c.649-290T>C		intron	N/A	ENSP00000363965.1
	ALPL	ENST00000540617.5	TSL:2	c.484-290T>C		intron	N/A	ENSP00000442672.1

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44268 AN: 151984 Hom.: 6553 Cov.: 32

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.290

Gnomad OTH AF: 0.283

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.291 AC: 44287 AN: 152102 Hom.: 6556 Cov.: 32 AF XY: 0.292 AC XY: 21700 AN XY: 74362

African (AFR) AF: 0.286 AC: 11878 AN: 41480

American (AMR) AF: 0.324 AC: 4951 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 852 AN: 3470

East Asian (EAS) AF: 0.322 AC: 1668 AN: 5174

South Asian (SAS) AF: 0.384 AC: 1854 AN: 4824

European-Finnish (FIN) AF: 0.233 AC: 2462 AN: 10584

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.290 AC: 19723 AN: 67972

Other (OTH) AF: 0.283 AC: 597 AN: 2110

Alfa AF: 0.295 Hom.: 8989

Bravo AF: 0.291

Asia WGS AF: 0.371 AC: 1287 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.3
DANN	Benign	0.35
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs10917008; hg19: chr1-21894307;