chr1-21573658-T-C

Variant names:

• chr1-21573658-T-C
• rs74063111
• NM_000478.6:c.863-7T>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.863-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,609,668 control chromosomes in the GnomAD database, including 21,059 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2828 hom., cov: 31)
  • Exomes 𝑓: 0.14 (18231 hom.)
• Consequence: ALPL NM_000478.6 splice_region, intron
• Scores: Splicing: ADA: 0.0001443
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.151
• 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: 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=-0.69).
• BP6: Variant 1-21573658-T-C is Benign according to our data. Variant chr1-21573658-T-C is described in ClinVar as Benign. ClinVar VariationId is 256237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.433 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.863-7T>C		splice_region intron	N/A	NP_000469.3
	ALPL	NM_001369803.2		c.863-7T>C		splice_region intron	N/A	NP_001356732.1	P05186-1
	ALPL	NM_001369804.2		c.863-7T>C		splice_region 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.863-7T>C		splice_region intron	N/A	ENSP00000363973.3	P05186-1
	ALPL	ENST00000374832.5	TSL:2	c.863-7T>C		splice_region intron	N/A	ENSP00000363965.1	P05186-1
	ALPL	ENST00000879459.1		c.743-7T>C		splice_region intron	N/A	ENSP00000549518.1

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26655 AN: 151666 Hom.: 2818 Cov.: 31

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.175

GnomAD2 exomes AF: 0.176 AC: 43747 AN: 247884 AF XY: 0.172

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.433

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.138 AC: 201893 AN: 1457884 Hom.: 18231 Cov.: 33 AF XY: 0.140 AC XY: 101317 AN XY: 725196

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.236 AC: 7873 AN: 33370

American (AMR) AF: 0.241 AC: 10709 AN: 44352

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 3598 AN: 26082

East Asian (EAS) AF: 0.508 AC: 20079 AN: 39508

South Asian (SAS) AF: 0.215 AC: 18486 AN: 85872

European-Finnish (FIN) AF: 0.174 AC: 9230 AN: 53142

Middle Eastern (MID) AF: 0.129 AC: 741 AN: 5734

European-Non Finnish (NFE) AF: 0.110 AC: 122037 AN: 1109556

Other (OTH) AF: 0.152 AC: 9140 AN: 60268

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.176 AC: 26701 AN: 151784 Hom.: 2828 Cov.: 31 AF XY: 0.183 AC XY: 13595 AN XY: 74126

African (AFR) AF: 0.227 AC: 9400 AN: 41376

American (AMR) AF: 0.224 AC: 3412 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 487 AN: 3472

East Asian (EAS) AF: 0.448 AC: 2283 AN: 5092

South Asian (SAS) AF: 0.232 AC: 1115 AN: 4800

European-Finnish (FIN) AF: 0.187 AC: 1970 AN: 10524

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 292

European-Non Finnish (NFE) AF: 0.111 AC: 7515 AN: 67952

Other (OTH) AF: 0.179 AC: 377 AN: 2108

Alfa AF: 0.127 Hom.: 584

Bravo AF: 0.183

Asia WGS AF: 0.322 AC: 1120 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Hypophosphatasia (3)
-	-	3	not provided (3)
-	-	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	-0.69
CADD	Benign	4.8
DANN	Benign	0.75
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0
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: rs74063111; hg19: chr1-21900151; COSMIC: COSV66376644; COSMIC: COSV66376644;