chr1-21563291-CG-C

Variant names:

• chr1-21563291-CG-C
• rs35423948
• NM_000478.6:c.472+12delG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000374840.8(ALPL):​c.472+8delG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,607,190 control chromosomes in the GnomAD database, including 20,642 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1634 hom., cov: 29)
  • Exomes 𝑓: 0.15 (19008 hom.)
• Consequence: ALPL ENST00000374840.8 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.351
• Publications: 2 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 -16 ACMG points.

• BP6: Variant 1-21563291-CG-C is Benign according to our data. Variant chr1-21563291-CG-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 295543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000374840.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPL	NM_000478.6	MANE Select	c.472+12delG		intron	N/A	NP_000469.3
	ALPL	NM_001369803.2		c.472+12delG		intron	N/A	NP_001356732.1
	ALPL	NM_001369804.2		c.472+12delG		intron	N/A	NP_001356733.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPL	ENST00000374840.8	TSL:1 MANE Select	c.472+8delG		splice_region intron	N/A	ENSP00000363973.3
	ALPL	ENST00000374832.5	TSL:2	c.472+8delG		splice_region intron	N/A	ENSP00000363965.1
	ALPL	ENST00000879459.1		c.352+8delG		splice_region intron	N/A	ENSP00000549518.1

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21079 AN: 152012 Hom.: 1634 Cov.: 29

Gnomad AFR AF: 0.0971

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0606

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.138

GnomAD2 exomes AF: 0.128 AC: 31336 AN: 245186 AF XY: 0.130

Gnomad AFR exome AF: 0.0945

Gnomad AMR exome AF: 0.0870

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.148

Gnomad NFE exome AF: 0.175

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.154 AC: 224548 AN: 1455060 Hom.: 19008 Cov.: 32 AF XY: 0.153 AC XY: 110669 AN XY: 722962

African (AFR) AF: 0.0936 AC: 3127 AN: 33408

American (AMR) AF: 0.0927 AC: 4127 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4631 AN: 25740

East Asian (EAS) AF: 0.000354 AC: 14 AN: 39584

South Asian (SAS) AF: 0.0623 AC: 5336 AN: 85678

European-Finnish (FIN) AF: 0.149 AC: 7871 AN: 52790

Middle Eastern (MID) AF: 0.206 AC: 1152 AN: 5588

European-Non Finnish (NFE) AF: 0.171 AC: 189675 AN: 1107662

Other (OTH) AF: 0.143 AC: 8615 AN: 60096

GnomAD4 genome AF: 0.139 AC: 21081 AN: 152130 Hom.: 1634 Cov.: 29 AF XY: 0.135 AC XY: 10046 AN XY: 74362

African (AFR) AF: 0.0971 AC: 4030 AN: 41516

American (AMR) AF: 0.125 AC: 1907 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 616 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.0609 AC: 293 AN: 4812

European-Finnish (FIN) AF: 0.141 AC: 1491 AN: 10592

Middle Eastern (MID) AF: 0.188 AC: 55 AN: 292

European-Non Finnish (NFE) AF: 0.180 AC: 12229 AN: 67970

Other (OTH) AF: 0.136 AC: 287 AN: 2110

Alfa AF: 0.164 Hom.: 412

Bravo AF: 0.134

Asia WGS AF: 0.0340 AC: 118 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	Hypophosphatasia (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.35
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: rs35423948; hg19: chr1-21889784;