rs10917008

Positions:

• chr1-21567814-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6	c.649-290T>C		intron_variant		ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.649-290T>C		intron_variant		1	NM_000478.6	P1
ALPL	ENST00000374832.5	c.649-290T>C		intron_variant		2		P1
ALPL	ENST00000539907.5	c.418-290T>C		intron_variant		2
ALPL	ENST00000540617.5	c.484-290T>C		intron_variant		2

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

Gnomad4 AFR AF: 0.286

Gnomad4 AMR AF: 0.324

Gnomad4 ASJ AF: 0.246

Gnomad4 EAS AF: 0.322

Gnomad4 SAS AF: 0.384

Gnomad4 FIN AF: 0.233

Gnomad4 NFE AF: 0.290

Gnomad4 OTH AF: 0.283

Alfa AF: 0.297 Hom.: 5720

Bravo AF: 0.291

Asia WGS AF: 0.371 AC: 1287 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.3
DANN	Benign	0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs10917008; hg19: chr1-21894307;