rs2242420

Variant names:

• chr1-21578036-C-T
• rs2242420
• NM_000478.6:c.*388C>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.*388C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 288,568 control chromosomes in the GnomAD database, including 1,923 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1056 hom., cov: 33)
  • Exomes 𝑓: 0.099 (867 hom.)
• Consequence: ALPL NM_000478.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.869
• Publications: 20 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• ALPL-related autosomal dominant hypophosphatasia

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

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Laboratory for Molecular Medicine, ClinGen
• 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)
• 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=-0.77).
• BP6: Variant 1-21578036-C-T is Benign according to our data. Variant chr1-21578036-C-T is described in ClinVar as Benign. ClinVar VariationId is 295566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 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.*388C>T		3_prime_UTR	Exon 12 of 12	NP_000469.3
	ALPL	NM_001369803.2		c.*388C>T		3_prime_UTR	Exon 12 of 12	NP_001356732.1	P05186-1
	ALPL	NM_001369804.2		c.*388C>T		3_prime_UTR	Exon 12 of 12	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.*388C>T		3_prime_UTR	Exon 12 of 12	ENSP00000363973.3	P05186-1
	ALPL	ENST00000879459.1		c.*388C>T		3_prime_UTR	Exon 10 of 10	ENSP00000549518.1
	ALPL	ENST00000540617.5	TSL:2	c.*388C>T		3_prime_UTR	Exon 11 of 11	ENSP00000442672.1	P05186-3

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17575 AN: 152140 Hom.: 1056 Cov.: 33

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.0689

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.140

GnomAD4 exome AF: 0.0989 AC: 13478 AN: 136308 Hom.: 867 Cov.: 0 AF XY: 0.0967 AC XY: 6843 AN XY: 70790

African (AFR) AF: 0.0959 AC: 441 AN: 4598

American (AMR) AF: 0.105 AC: 581 AN: 5516

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 604 AN: 3922

East Asian (EAS) AF: 0.167 AC: 1215 AN: 7254

South Asian (SAS) AF: 0.0582 AC: 996 AN: 17112

European-Finnish (FIN) AF: 0.0978 AC: 735 AN: 7512

Middle Eastern (MID) AF: 0.164 AC: 87 AN: 532

European-Non Finnish (NFE) AF: 0.0972 AC: 7982 AN: 82144

Other (OTH) AF: 0.108 AC: 837 AN: 7718

GnomAD4 genome AF: 0.115 AC: 17577 AN: 152260 Hom.: 1056 Cov.: 33 AF XY: 0.115 AC XY: 8553 AN XY: 74458

African (AFR) AF: 0.102 AC: 4253 AN: 41550

American (AMR) AF: 0.117 AC: 1788 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 638 AN: 3472

East Asian (EAS) AF: 0.191 AC: 984 AN: 5164

South Asian (SAS) AF: 0.0689 AC: 333 AN: 4834

European-Finnish (FIN) AF: 0.113 AC: 1200 AN: 10618

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7905 AN: 68018

Other (OTH) AF: 0.138 AC: 292 AN: 2110

Alfa AF: 0.120 Hom.: 3532

Bravo AF: 0.119

Asia WGS AF: 0.107 AC: 372 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hypophosphatasia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.7
DANN	Benign	0.77
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: rs2242420; hg19: chr1-21904529; COSMIC: COSV66376684; COSMIC: COSV66376684;