rs885813

Variant names:

• chr1-21550581-C-T
• rs885813
• NM_000478.6:c.-104-3397C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000478.6(ALPL):​c.-104-3397C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 151,810 control chromosomes in the GnomAD database, including 11,067 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.37 (11067 hom., cov: 31)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.993
• Publications: 8 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

ENSG00000289715 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6	c.-104-3397C>T		intron_variant	Intron 1 of 11	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8	c.-104-3397C>T		intron_variant	Intron 1 of 11	1	NM_000478.6	ENSP00000363973.3
ENSG00000289715	ENST00000696766.1	c.119+3059C>T		intron_variant	Intron 1 of 1			ENSP00000512858.1

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56487 AN: 151692 Hom.: 11058 Cov.: 31

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.390

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

GnomAD4 genome AF: 0.372 AC: 56518 AN: 151810 Hom.: 11067 Cov.: 31 AF XY: 0.366 AC XY: 27158 AN XY: 74154

African (AFR) AF: 0.299 AC: 12370 AN: 41334

American (AMR) AF: 0.343 AC: 5231 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1734 AN: 3470

East Asian (EAS) AF: 0.167 AC: 863 AN: 5166

South Asian (SAS) AF: 0.266 AC: 1277 AN: 4802

European-Finnish (FIN) AF: 0.368 AC: 3885 AN: 10548

Middle Eastern (MID) AF: 0.476 AC: 139 AN: 292

European-Non Finnish (NFE) AF: 0.438 AC: 29774 AN: 67922

Other (OTH) AF: 0.390 AC: 822 AN: 2108

Alfa AF: 0.422 Hom.: 58835

Bravo AF: 0.369

Asia WGS AF: 0.240 AC: 835 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.4
DANN	Benign	0.40
PhyloP100		-0.99
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: rs885813; hg19: chr1-21877074;