rs3738098

Variant names:

• chr1-21568292-G-T
• rs3738098
• NM_000478.6:c.792+45G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-21568292-G-T
• chr1-21568292-G-C

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.792+45G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0939 in 1,612,352 control chromosomes in the GnomAD database, including 13,038 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (1214 hom., cov: 31)
  • Exomes 𝑓: 0.095 (11824 hom.)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.33
• Publications: 6 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=-0.86).
• BP6: Variant 1-21568292-G-T is Benign according to our data. Variant chr1-21568292-G-T is described in ClinVar as Benign. ClinVar VariationId is 256231.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.792+45G>T		intron	N/A	NP_000469.3
	ALPL	NM_001369803.2		c.792+45G>T		intron	N/A	NP_001356732.1	P05186-1
	ALPL	NM_001369804.2		c.792+45G>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.792+45G>T		intron	N/A	ENSP00000363973.3	P05186-1
	ALPL	ENST00000374832.5	TSL:2	c.792+45G>T		intron	N/A	ENSP00000363965.1	P05186-1
	ALPL	ENST00000879459.1		c.672+45G>T		intron	N/A	ENSP00000549518.1

Frequencies

GnomAD3 genomes AF: 0.0856 AC: 12998 AN: 151898 Hom.: 1207 Cov.: 31

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.0701

Gnomad NFE AF: 0.0653

Gnomad OTH AF: 0.0989

GnomAD2 exomes AF: 0.135 AC: 33552 AN: 249012 AF XY: 0.134

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.220

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.443

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.0642

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.0947 AC: 138320 AN: 1460334 Hom.: 11824 Cov.: 32 AF XY: 0.0977 AC XY: 71000 AN XY: 726402

African (AFR) AF: 0.0125 AC: 418 AN: 33460

American (AMR) AF: 0.213 AC: 9458 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 3055 AN: 26104

East Asian (EAS) AF: 0.511 AC: 20243 AN: 39652

South Asian (SAS) AF: 0.211 AC: 18133 AN: 86068

European-Finnish (FIN) AF: 0.0981 AC: 5224 AN: 53250

Middle Eastern (MID) AF: 0.0839 AC: 465 AN: 5544

European-Non Finnish (NFE) AF: 0.0676 AC: 75114 AN: 1111444

Other (OTH) AF: 0.103 AC: 6210 AN: 60306

GnomAD4 genome AF: 0.0856 AC: 13017 AN: 152018 Hom.: 1214 Cov.: 31 AF XY: 0.0940 AC XY: 6984 AN XY: 74286

African (AFR) AF: 0.0170 AC: 706 AN: 41518

American (AMR) AF: 0.174 AC: 2656 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 416 AN: 3470

East Asian (EAS) AF: 0.453 AC: 2317 AN: 5112

South Asian (SAS) AF: 0.226 AC: 1084 AN: 4802

European-Finnish (FIN) AF: 0.104 AC: 1098 AN: 10556

Middle Eastern (MID) AF: 0.0685 AC: 20 AN: 292

European-Non Finnish (NFE) AF: 0.0653 AC: 4435 AN: 67968

Other (OTH) AF: 0.104 AC: 219 AN: 2114

Alfa AF: 0.0614 Hom.: 196

Bravo AF: 0.0881

Asia WGS AF: 0.306 AC: 1063 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	Infantile hypophosphatasia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	11
DANN	Benign	0.75
PhyloP100		1.3
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: rs3738098; hg19: chr1-21894785; COSMIC: COSV107493307; COSMIC: COSV107493307;