rs4654760

Variant names:

• chr1-21576687-C-T
• rs4654760
• NM_000478.6:c.1309+46C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-21576687-C-T
• chr1-21576687-C-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.1309+46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0924 in 1,610,428 control chromosomes in the GnomAD database, including 12,691 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (1246 hom., cov: 32)
  • Exomes 𝑓: 0.093 (11445 hom.)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.24
• Publications: 7 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=-0.91).
• BP6: Variant 1-21576687-C-T is Benign according to our data. Variant chr1-21576687-C-T is described in ClinVar as Benign. ClinVar VariationId is 256227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.441 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.1309+46C>T		intron	N/A	NP_000469.3
	ALPL	NM_001369803.2		c.1309+46C>T		intron	N/A	NP_001356732.1	P05186-1
	ALPL	NM_001369804.2		c.1309+46C>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.1309+46C>T		intron	N/A	ENSP00000363973.3	P05186-1
	ALPL	ENST00000374832.5	TSL:2	c.1309+46C>T		intron	N/A	ENSP00000363965.1	P05186-1
	ALPL	ENST00000879459.1		c.1189+46C>T		intron	N/A	ENSP00000549518.1

Frequencies

GnomAD3 genomes AF: 0.0860 AC: 13059 AN: 151896 Hom.: 1235 Cov.: 32

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.0703

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.454

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0649

Gnomad OTH AF: 0.0981

GnomAD2 exomes AF: 0.133 AC: 33227 AN: 249746 AF XY: 0.131

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.223

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.447

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.0639

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.0931 AC: 135730 AN: 1458414 Hom.: 11445 Cov.: 31 AF XY: 0.0956 AC XY: 69314 AN XY: 725310

African (AFR) AF: 0.0123 AC: 412 AN: 33398

American (AMR) AF: 0.214 AC: 9547 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 2778 AN: 26028

East Asian (EAS) AF: 0.509 AC: 20123 AN: 39554

South Asian (SAS) AF: 0.193 AC: 16634 AN: 86004

European-Finnish (FIN) AF: 0.0985 AC: 5229 AN: 53088

Middle Eastern (MID) AF: 0.0812 AC: 467 AN: 5748

European-Non Finnish (NFE) AF: 0.0671 AC: 74420 AN: 1109860

Other (OTH) AF: 0.102 AC: 6120 AN: 60158

GnomAD4 genome AF: 0.0861 AC: 13086 AN: 152014 Hom.: 1246 Cov.: 32 AF XY: 0.0949 AC XY: 7047 AN XY: 74284

African (AFR) AF: 0.0175 AC: 726 AN: 41468

American (AMR) AF: 0.185 AC: 2825 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 379 AN: 3472

East Asian (EAS) AF: 0.456 AC: 2337 AN: 5126

South Asian (SAS) AF: 0.208 AC: 997 AN: 4802

European-Finnish (FIN) AF: 0.105 AC: 1114 AN: 10592

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0648 AC: 4405 AN: 67964

Other (OTH) AF: 0.104 AC: 220 AN: 2112

Alfa AF: 0.0754 Hom.: 118

Bravo AF: 0.0886

Asia WGS AF: 0.308 AC: 1068 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.36
DANN	Benign	0.57
PhyloP100		-1.2
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: rs4654760; hg19: chr1-21903180; COSMIC: COSV66376245;