rs3200255

Variant names:

• chr1-21573678-A-G
• rs3200255
• NM_000478.6:c.876A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-21573678-A-G
• chr1-21573678-A-C
• chr1-21573678-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000478.6(ALPL):​c.876A>G​(p.Pro292Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,612,332 control chromosomes in the GnomAD database, including 22,830 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3281 hom., cov: 31)
  • Exomes 𝑓: 0.14 (19549 hom.)
• Consequence: ALPL NM_000478.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -6.95
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-21573678-A-G is Benign according to our data. Variant chr1-21573678-A-G is described in ClinVar as Benign. ClinVar VariationId is 256238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.95 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.435 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.876A>G	p.Pro292Pro	synonymous	Exon 9 of 12	NP_000469.3
	ALPL	NM_001369803.2		c.876A>G	p.Pro292Pro	synonymous	Exon 9 of 12	NP_001356732.1	P05186-1
	ALPL	NM_001369804.2		c.876A>G	p.Pro292Pro	synonymous	Exon 9 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.876A>G	p.Pro292Pro	synonymous	Exon 9 of 12	ENSP00000363973.3	P05186-1
	ALPL	ENST00000374832.5	TSL:2	c.876A>G	p.Pro292Pro	synonymous	Exon 9 of 12	ENSP00000363965.1	P05186-1
	ALPL	ENST00000879459.1		c.756A>G	p.Pro252Pro	synonymous	Exon 7 of 10	ENSP00000549518.1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28657 AN: 151840 Hom.: 3269 Cov.: 31

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.449

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.185

GnomAD2 exomes AF: 0.184 AC: 46024 AN: 249588 AF XY: 0.179

Gnomad AFR exome AF: 0.266

Gnomad AMR exome AF: 0.251

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.436

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.158

GnomAD4 exome AF: 0.145 AC: 211698 AN: 1460372 Hom.: 19549 Cov.: 33 AF XY: 0.146 AC XY: 105880 AN XY: 726498

African (AFR) AF: 0.277 AC: 9271 AN: 33448

American (AMR) AF: 0.247 AC: 10986 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3628 AN: 26118

East Asian (EAS) AF: 0.508 AC: 20139 AN: 39618

South Asian (SAS) AF: 0.216 AC: 18594 AN: 86080

European-Finnish (FIN) AF: 0.180 AC: 9577 AN: 53270

Middle Eastern (MID) AF: 0.135 AC: 776 AN: 5762

European-Non Finnish (NFE) AF: 0.116 AC: 129154 AN: 1111210

Other (OTH) AF: 0.159 AC: 9573 AN: 60340

GnomAD4 genome AF: 0.189 AC: 28707 AN: 151960 Hom.: 3281 Cov.: 31 AF XY: 0.196 AC XY: 14561 AN XY: 74238

African (AFR) AF: 0.263 AC: 10883 AN: 41432

American (AMR) AF: 0.228 AC: 3480 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 489 AN: 3470

East Asian (EAS) AF: 0.450 AC: 2308 AN: 5128

South Asian (SAS) AF: 0.231 AC: 1111 AN: 4808

European-Finnish (FIN) AF: 0.191 AC: 2023 AN: 10566

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

European-Non Finnish (NFE) AF: 0.116 AC: 7874 AN: 67970

Other (OTH) AF: 0.188 AC: 398 AN: 2112

Alfa AF: 0.114 Hom.: 726

Bravo AF: 0.197

Asia WGS AF: 0.327 AC: 1136 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	4	Hypophosphatasia (4)
-	-	1	Adult hypophosphatasia (1)
-	-	1	Childhood hypophosphatasia (1)
-	-	1	Infantile hypophosphatasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.028
DANN	Benign	0.45
PhyloP100		-6.9
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: rs3200255; hg19: chr1-21900171; COSMIC: COSV66376656; COSMIC: COSV66376656;