1-21554001-G-T

Variant names:

• chr1-21554001-G-T
• rs528218843
• ENST00000696766.1:c.143G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The ENST00000696766.1(ENSG00000289715):​c.143G>T​(p.Ter48Leuext*?) variant causes a stop lost, splice region change. The variant allele was found at a frequency of 0.00000101 in 989,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: ENSG00000289715 ENST00000696766.1 stop_lost, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.11
• Publications: 0 publications found

Genes affected

ENSG00000289715 (HGNC:):

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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in ENST00000696766.1

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000696766.1. 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.-81G>T		5_prime_UTR	Exon 2 of 12	NP_000469.3
	ALPL	NM_001369803.2		c.-81G>T		5_prime_UTR	Exon 2 of 12	NP_001356732.1	P05186-1
	ALPL	NM_001369804.2		c.-81G>T		5_prime_UTR	Exon 2 of 12	NP_001356733.1	P05186-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000289715	ENST00000696766.1		c.143G>T	p.Ter48Leuext*?	stop_lost splice_region	Exon 2 of 2	ENSP00000512858.1	A0A8Q3SIZ7
	ALPL	ENST00000374840.8	TSL:1 MANE Select	c.-81G>T		5_prime_UTR	Exon 2 of 12	ENSP00000363973.3	P05186-1
	ALPL	ENST00000374832.5	TSL:2	c.-81G>T		5_prime_UTR	Exon 2 of 12	ENSP00000363965.1	P05186-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000101 AC: 1 AN: 989708 Hom.: 0 Cov.: 13 AF XY: 0.00000195 AC XY: 1 AN XY: 513176

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

African (AFR) AF: 0.00 AC: 0 AN: 24062

American (AMR) AF: 0.00 AC: 0 AN: 43998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23188

East Asian (EAS) AF: 0.00 AC: 0 AN: 37526

South Asian (SAS) AF: 0.0000130 AC: 1 AN: 76754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3440

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 682762

Other (OTH) AF: 0.00 AC: 0 AN: 44870

⚠️ 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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.89
PhyloP100		4.1
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs528218843; hg19: chr1-21880494;