rs885813

Positions:

• chr1-21550581-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
ALPL	NM_000478.6	c.-104-3397C>T		intron_variant		ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.-104-3397C>T		intron_variant		1	NM_000478.6	P1
	ENST00000696766.1	c.119+3059C>T		intron_variant				P1

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

Gnomad4 AFR AF: 0.299

Gnomad4 AMR AF: 0.343

Gnomad4 ASJ AF: 0.500

Gnomad4 EAS AF: 0.167

Gnomad4 SAS AF: 0.266

Gnomad4 FIN AF: 0.368

Gnomad4 NFE AF: 0.438

Gnomad4 OTH AF: 0.390

Alfa AF: 0.431 Hom.: 29781

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs885813; hg19: chr1-21877074;