1-21558702-C-T

Variant names:

• chr1-21558702-C-T
• rs3767155
• NM_000478.6:c.62-1924C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000478.6(ALPL):​c.62-1924C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 151,738 control chromosomes in the GnomAD database, including 8,454 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 0.33 (8454 hom., cov: 32)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.908

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6	c.62-1924C>T		intron_variant	Intron 2 of 11	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8	c.62-1924C>T		intron_variant	Intron 2 of 11	1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49481 AN: 151620 Hom.: 8453 Cov.: 32

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.350

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.372

Gnomad OTH AF: 0.323

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

GnomAD4 genome AF: 0.326 AC: 49487 AN: 151738 Hom.: 8454 Cov.: 32 AF XY: 0.329 AC XY: 24397 AN XY: 74128

Gnomad4 AFR AF: 0.211

Gnomad4 AMR AF: 0.364

Gnomad4 ASJ AF: 0.362

Gnomad4 EAS AF: 0.349

Gnomad4 SAS AF: 0.452

Gnomad4 FIN AF: 0.348

Gnomad4 NFE AF: 0.372

Gnomad4 OTH AF: 0.323

Alfa AF: 0.356 Hom.: 12691

Bravo AF: 0.315

Asia WGS AF: 0.405 AC: 1407 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.73
DANN	Benign	0.59

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: rs3767155; hg19: chr1-21885195;