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. The variant received -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
• Publications: 4 publications found

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]

ALPL Gene-Disease associations (from GenCC):

• adult hypophosphatasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
• childhood hypophosphatasia

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, ClinGen, Orphanet
• hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, G2P
• infantile hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia
• odontohypophosphatasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• perinatal lethal hypophosphatasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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

GnomAD2 exomes AF: 0.178 AC: 42941 AN: 241068 AF XY: 0.173

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.274 AC: 9008 AN: 32920

American (AMR) AF: 0.242 AC: 10592 AN: 43742

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3537 AN: 25910

East Asian (EAS) AF: 0.507 AC: 19797 AN: 39052

South Asian (SAS) AF: 0.214 AC: 18094 AN: 84742

European-Finnish (FIN) AF: 0.177 AC: 9321 AN: 52552

Middle Eastern (MID) AF: 0.134 AC: 707 AN: 5288

European-Non Finnish (NFE) AF: 0.113 AC: 124450 AN: 1101348

Other (OTH) AF: 0.156 AC: 9309 AN: 59734

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.263 AC: 10886 AN: 41404

American (AMR) AF: 0.229 AC: 3492 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 489 AN: 3468

East Asian (EAS) AF: 0.451 AC: 2319 AN: 5138

South Asian (SAS) AF: 0.233 AC: 1120 AN: 4798

European-Finnish (FIN) AF: 0.192 AC: 2025 AN: 10540

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 292

European-Non Finnish (NFE) AF: 0.116 AC: 7874 AN: 67922

Other (OTH) AF: 0.189 AC: 399 AN: 2106

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
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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