rs6658127

Positions:

• chr1-21548897-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000478.6(ALPL):​c.-104-5081G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 152,000 control chromosomes in the GnomAD database, including 6,739 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 0.29 (6739 hom., cov: 32)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.183

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6	c.-104-5081G>A		intron_variant		ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.-104-5081G>A		intron_variant		1	NM_000478.6	P1
	ENST00000696766.1	c.119+1375G>A		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43333 AN: 151884 Hom.: 6736 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.289

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

GnomAD4 genome AF: 0.285 AC: 43335 AN: 152000 Hom.: 6739 Cov.: 32 AF XY: 0.288 AC XY: 21397 AN XY: 74274

Gnomad4 AFR AF: 0.162

Gnomad4 AMR AF: 0.331

Gnomad4 ASJ AF: 0.302

Gnomad4 EAS AF: 0.329

Gnomad4 SAS AF: 0.430

Gnomad4 FIN AF: 0.313

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.289

Alfa AF: 0.239 Hom.: 1050

Bravo AF: 0.275

Asia WGS AF: 0.374 AC: 1299 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.6
DANN	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs6658127; hg19: chr1-21875390;