rs74063111

Variant names:

• chr1-21573658-T-C
• rs74063111
• NM_000478.6:c.863-7T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-21573658-T-C
• chr1-21573658-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000478.6(ALPL):​c.863-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,609,668 control chromosomes in the GnomAD database, including 21,059 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2828 hom., cov: 31)
  • Exomes 𝑓: 0.14 (18231 hom.)
• Consequence: ALPL NM_000478.6 splice_region, intron
• Scores: Splicing: ADA: 0.0001443
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.151

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 1-21573658-T-C is Benign according to our data. Variant chr1-21573658-T-C is described in ClinVar as [Benign]. Clinvar id is 256237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21573658-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6	c.863-7T>C		splice_region_variant, intron_variant	Intron 8 of 11	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8	c.863-7T>C		splice_region_variant, intron_variant	Intron 8 of 11	1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26655 AN: 151666 Hom.: 2818 Cov.: 31

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.175

GnomAD3 exomes AF: 0.176 AC: 43747 AN: 247884 Hom.: 4949 AF XY: 0.172 AC XY: 23072 AN XY: 134068

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.433

Gnomad SAS exome AF: 0.211

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.138 AC: 201893 AN: 1457884 Hom.: 18231 Cov.: 33 AF XY: 0.140 AC XY: 101317 AN XY: 725196

Gnomad4 AFR exome AF: 0.236

Gnomad4 AMR exome AF: 0.241

Gnomad4 ASJ exome AF: 0.138

Gnomad4 EAS exome AF: 0.508

Gnomad4 SAS exome AF: 0.215

Gnomad4 FIN exome AF: 0.174

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.152

GnomAD4 genome AF: 0.176 AC: 26701 AN: 151784 Hom.: 2828 Cov.: 31 AF XY: 0.183 AC XY: 13595 AN XY: 74126

Gnomad4 AFR AF: 0.227

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.140

Gnomad4 EAS AF: 0.448

Gnomad4 SAS AF: 0.232

Gnomad4 FIN AF: 0.187

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.179

Alfa AF: 0.127 Hom.: 584

Bravo AF: 0.183

Asia WGS AF: 0.322 AC: 1120 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Oct 17, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Aug 20, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypophosphatasia Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 20, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Infantile hypophosphatasia Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Adult hypophosphatasia Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Childhood hypophosphatasia Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	4.8
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0
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: rs74063111; hg19: chr1-21900151; COSMIC: COSV66376644; COSMIC: COSV66376644;