1-21570394-G-T

Variant names:

• chr1-21570394-G-T
• rs2275377
• NM_000478.6:c.862+20G>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.862+20G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,611,926 control chromosomes in the GnomAD database, including 21,827 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3131 hom., cov: 33)
  • Exomes 𝑓: 0.14 (18696 hom.)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.772
• Publications: 13 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, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
• ALPL-related autosomal dominant hypophosphatasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• childhood hypophosphatasia

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Orphanet
• ALPL-related autosomal recessive hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hypophosphatasia

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, 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=-0.9).
• BP6: Variant 1-21570394-G-T is Benign according to our data. Variant chr1-21570394-G-T is described in ClinVar as Benign. ClinVar VariationId is 256233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000478.6. 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.862+20G>T		intron	N/A	NP_000469.3
	ALPL	NM_001369803.2		c.862+20G>T		intron	N/A	NP_001356732.1	P05186-1
	ALPL	NM_001369804.2		c.862+20G>T		intron	N/A	NP_001356733.1	P05186-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPL	ENST00000374840.8	TSL:1 MANE Select	c.862+20G>T		intron	N/A	ENSP00000363973.3	P05186-1
	ALPL	ENST00000374832.5	TSL:2	c.862+20G>T		intron	N/A	ENSP00000363965.1	P05186-1
	ALPL	ENST00000879459.1		c.742+20G>T		intron	N/A	ENSP00000549518.1

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27822 AN: 151946 Hom.: 3118 Cov.: 33

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.178

GnomAD2 exomes AF: 0.183 AC: 45705 AN: 250058 AF XY: 0.178

Gnomad AFR exome AF: 0.255

Gnomad AMR exome AF: 0.250

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.442

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.140 AC: 204817 AN: 1459862 Hom.: 18696 Cov.: 32 AF XY: 0.141 AC XY: 102701 AN XY: 726352

African (AFR) AF: 0.265 AC: 8860 AN: 33424

American (AMR) AF: 0.245 AC: 10946 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 3657 AN: 26112

East Asian (EAS) AF: 0.511 AC: 20247 AN: 39656

South Asian (SAS) AF: 0.217 AC: 18678 AN: 86156

European-Finnish (FIN) AF: 0.175 AC: 9337 AN: 53254

Middle Eastern (MID) AF: 0.131 AC: 752 AN: 5758

European-Non Finnish (NFE) AF: 0.111 AC: 123005 AN: 1110584

Other (OTH) AF: 0.155 AC: 9335 AN: 60328

GnomAD4 genome AF: 0.183 AC: 27873 AN: 152064 Hom.: 3131 Cov.: 33 AF XY: 0.191 AC XY: 14174 AN XY: 74312

African (AFR) AF: 0.252 AC: 10449 AN: 41502

American (AMR) AF: 0.225 AC: 3433 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 494 AN: 3472

East Asian (EAS) AF: 0.454 AC: 2328 AN: 5130

South Asian (SAS) AF: 0.234 AC: 1128 AN: 4820

European-Finnish (FIN) AF: 0.187 AC: 1983 AN: 10580

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7534 AN: 67978

Other (OTH) AF: 0.182 AC: 384 AN: 2114

Alfa AF: 0.145 Hom.: 358

Bravo AF: 0.191

Asia WGS AF: 0.327 AC: 1137 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Adult hypophosphatasia (1)
-	-	1	Childhood hypophosphatasia (1)
-	-	1	Hypophosphatasia (1)
-	-	1	Infantile hypophosphatasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.65
PhyloP100		-0.77
PromoterAI		-0.049	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2275377; hg19: chr1-21896887; COSMIC: COSV66376057; COSMIC: COSV66376057;