rs74063110

Variant names:

• chr1-21573619-G-A
• rs74063110
• NM_000478.6:c.863-46G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-21573619-G-A
• chr1-21573619-G-C
• chr1-21573619-G-T

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.863-46G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,597,136 control chromosomes in the GnomAD database, including 22,447 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3297 hom., cov: 31)
  • Exomes 𝑓: 0.14 (19150 hom.)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.220

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=-0.84).
• BP6: Variant 1-21573619-G-A is Benign according to our data. Variant chr1-21573619-G-A is described in ClinVar as [Benign]. Clinvar id is 256236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6	c.863-46G>A		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.863-46G>A		intron_variant	Intron 8 of 11	1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28695 AN: 151730 Hom.: 3285 Cov.: 31

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.178 AC: 42941 AN: 241068 Hom.: 4875 AF XY: 0.173 AC XY: 22557 AN XY: 130386

Gnomad AFR exome AF: 0.255

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.427

Gnomad SAS exome AF: 0.207

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.142 AC: 204815 AN: 1445288 Hom.: 19150 Cov.: 32 AF XY: 0.143 AC XY: 102533 AN XY: 718954

Gnomad4 AFR exome AF: 0.274

Gnomad4 AMR exome AF: 0.242

Gnomad4 ASJ exome AF: 0.137

Gnomad4 EAS exome AF: 0.507

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.113

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.189 AC: 28746 AN: 151848 Hom.: 3297 Cov.: 31 AF XY: 0.197 AC XY: 14596 AN XY: 74184

Gnomad4 AFR AF: 0.263

Gnomad4 AMR AF: 0.229

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.451

Gnomad4 SAS AF: 0.233

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.189

Alfa AF: 0.140 Hom.: 331

Bravo AF: 0.197

Asia WGS AF: 0.327 AC: 1136 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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	-0.84
CADD	Benign	12
DANN	Benign	0.78

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: rs74063110; hg19: chr1-21900112; COSMIC: COSV66376060; COSMIC: COSV66376060;