NM_000478.6:c.997+128A>G

Variant names:

• chr1-21573927-A-G
• rs2275370
• NM_000478.6:c.997+128A>G

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.997+128A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.775 in 1,510,290 control chromosomes in the GnomAD database, including 454,038 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44445 hom., cov: 32)
  • Exomes 𝑓: 0.78 (409593 hom.)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.386
• Publications: 14 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=-0.91).
• BP6: Variant 1-21573927-A-G is Benign according to our data. Variant chr1-21573927-A-G is described in ClinVar as Benign. ClinVar VariationId is 1236467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6	c.997+128A>G		intron_variant	Intron 9 of 11	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8	c.997+128A>G		intron_variant	Intron 9 of 11	1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes AF: 0.764 AC: 116101 AN: 152058 Hom.: 44408 Cov.: 32

Gnomad AFR AF: 0.707

Gnomad AMI AF: 0.727

Gnomad AMR AF: 0.792

Gnomad ASJ AF: 0.742

Gnomad EAS AF: 0.803

Gnomad SAS AF: 0.769

Gnomad FIN AF: 0.813

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.783

Gnomad OTH AF: 0.744

GnomAD4 exome AF: 0.776 AC: 1054045 AN: 1358114 Hom.: 409593 AF XY: 0.776 AC XY: 515839 AN XY: 665040

African (AFR) AF: 0.704 AC: 21742 AN: 30880

American (AMR) AF: 0.812 AC: 26438 AN: 32548

Ashkenazi Jewish (ASJ) AF: 0.746 AC: 16835 AN: 22552

East Asian (EAS) AF: 0.810 AC: 29005 AN: 35830

South Asian (SAS) AF: 0.751 AC: 54766 AN: 72904

European-Finnish (FIN) AF: 0.816 AC: 35845 AN: 43902

Middle Eastern (MID) AF: 0.717 AC: 3907 AN: 5450

European-Non Finnish (NFE) AF: 0.777 AC: 822379 AN: 1057830

Other (OTH) AF: 0.767 AC: 43128 AN: 56218

GnomAD4 genome AF: 0.763 AC: 116183 AN: 152176 Hom.: 44445 Cov.: 32 AF XY: 0.768 AC XY: 57115 AN XY: 74388

African (AFR) AF: 0.706 AC: 29327 AN: 41514

American (AMR) AF: 0.793 AC: 12130 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.742 AC: 2573 AN: 3466

East Asian (EAS) AF: 0.803 AC: 4156 AN: 5174

South Asian (SAS) AF: 0.768 AC: 3708 AN: 4826

European-Finnish (FIN) AF: 0.813 AC: 8598 AN: 10582

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.783 AC: 53250 AN: 67996

Other (OTH) AF: 0.744 AC: 1573 AN: 2114

Alfa AF: 0.769 Hom.: 120583

Bravo AF: 0.755

Asia WGS AF: 0.782 AC: 2717 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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 09, 2018

GeneDx

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	-0.91
CADD	Benign	3.4
DANN	Benign	0.58
PhyloP100		-0.39
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: rs2275370; hg19: chr1-21900420; COSMIC: COSV66376031; COSMIC: COSV66376031;