rs1780329

Variant names:

• chr1-21576457-C-A
• rs1780329
• NM_000478.6:c.1190-65C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-21576457-C-A
• chr1-21576457-C-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.1190-65C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,585,492 control chromosomes in the GnomAD database, including 36,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5390 hom., cov: 31)
  • Exomes 𝑓: 0.19 (30678 hom.)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.873
• Publications: 16 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 1-21576457-C-A is Benign according to our data. Variant chr1-21576457-C-A is described in ClinVar as Benign. ClinVar VariationId is 1177605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6	c.1190-65C>A		intron_variant	Intron 10 of 11	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8	c.1190-65C>A		intron_variant	Intron 10 of 11	1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37615 AN: 151688 Hom.: 5377 Cov.: 31

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.469

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.236

GnomAD4 exome AF: 0.195 AC: 279081 AN: 1433684 Hom.: 30678 AF XY: 0.195 AC XY: 138347 AN XY: 709848

African (AFR) AF: 0.350 AC: 11493 AN: 32812

American (AMR) AF: 0.278 AC: 11839 AN: 42596

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 3943 AN: 25078

East Asian (EAS) AF: 0.524 AC: 20494 AN: 39098

South Asian (SAS) AF: 0.248 AC: 20766 AN: 83756

European-Finnish (FIN) AF: 0.250 AC: 13185 AN: 52676

Middle Eastern (MID) AF: 0.170 AC: 862 AN: 5068

European-Non Finnish (NFE) AF: 0.168 AC: 184143 AN: 1093610

Other (OTH) AF: 0.209 AC: 12356 AN: 58990

GnomAD4 genome AF: 0.248 AC: 37670 AN: 151808 Hom.: 5390 Cov.: 31 AF XY: 0.254 AC XY: 18830 AN XY: 74202

African (AFR) AF: 0.350 AC: 14474 AN: 41332

American (AMR) AF: 0.278 AC: 4240 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 548 AN: 3470

East Asian (EAS) AF: 0.470 AC: 2407 AN: 5124

South Asian (SAS) AF: 0.257 AC: 1237 AN: 4812

European-Finnish (FIN) AF: 0.268 AC: 2835 AN: 10562

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11251 AN: 67924

Other (OTH) AF: 0.241 AC: 508 AN: 2112

Alfa AF: 0.204 Hom.: 5453

Bravo AF: 0.253

Asia WGS AF: 0.356 AC: 1238 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 20, 2018

GeneDx

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	1.5
DANN	Benign	0.75
PhyloP100		-0.87
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: rs1780329; hg19: chr1-21902950; COSMIC: COSV66376181;