1-21540336-T-C

Variant names:

• chr1-21540336-T-C
• rs1256341
• NM_000478.6:c.-104-13642T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000478.6(ALPL):​c.-104-13642T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 152,076 control chromosomes in the GnomAD database, including 5,330 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (5330 hom., cov: 32)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.44
• Publications: 5 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: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
• childhood hypophosphatasia

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, ClinGen, Orphanet
• hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, G2P
• infantile hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.289 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPL	NM_000478.6	MANE Select	c.-104-13642T>C		intron	N/A	NP_000469.3
	ALPL	NM_001369804.2		c.-104-13642T>C		intron	N/A	NP_001356733.1
	ALPL	NM_001369805.2		c.-104-13642T>C		intron	N/A	NP_001356734.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPL	ENST00000374840.8	TSL:1 MANE Select	c.-104-13642T>C		intron	N/A	ENSP00000363973.3
	ALPL	ENST00000540617.5	TSL:2	c.-104-20290T>C		intron	N/A	ENSP00000442672.1
	ALPL	ENST00000539907.5	TSL:2	c.-54-20290T>C		intron	N/A	ENSP00000437674.1

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39391 AN: 151958 Hom.: 5330 Cov.: 32

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.375

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.214

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.279

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.259 AC: 39396 AN: 152076 Hom.: 5330 Cov.: 32 AF XY: 0.254 AC XY: 18850 AN XY: 74344

African (AFR) AF: 0.236 AC: 9775 AN: 41486

American (AMR) AF: 0.251 AC: 3834 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 1302 AN: 3470

East Asian (EAS) AF: 0.150 AC: 777 AN: 5166

South Asian (SAS) AF: 0.126 AC: 606 AN: 4820

European-Finnish (FIN) AF: 0.214 AC: 2262 AN: 10576

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.292 AC: 19844 AN: 67954

Other (OTH) AF: 0.276 AC: 580 AN: 2102

Alfa AF: 0.289 Hom.: 11083

Bravo AF: 0.263

Asia WGS AF: 0.142 AC: 490 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.0
DANN	Benign	0.83
PhyloP100		-3.4
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: rs1256341; hg19: chr1-21866829;