rs7523855

Positions:

• chr1-21514393-C-T

Variant summary

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

The NM_000478.6(ALPL):​c.-105+4876C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 152,144 control chromosomes in the GnomAD database, including 8,788 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 0.32 (8788 hom., cov: 32)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.90

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALPL	NM_000478.6	c.-105+4876C>T		intron_variant		ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8	c.-105+4876C>T		intron_variant		1	NM_000478.6	ENSP00000363973	P1
ALPL	ENST00000539907.5	c.-55+4876C>T		intron_variant		2		ENSP00000437674
ALPL	ENST00000540617.5	c.-105+4876C>T		intron_variant		2		ENSP00000442672
ALPL	ENST00000468526.1	n.121+4876C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49404 AN: 152026 Hom.: 8790 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.339

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

GnomAD4 genome AF: 0.325 AC: 49402 AN: 152144 Hom.: 8788 Cov.: 32 AF XY: 0.331 AC XY: 24595 AN XY: 74360

Gnomad4 AFR AF: 0.169

Gnomad4 AMR AF: 0.409

Gnomad4 ASJ AF: 0.344

Gnomad4 EAS AF: 0.474

Gnomad4 SAS AF: 0.465

Gnomad4 FIN AF: 0.405

Gnomad4 NFE AF: 0.366

Gnomad4 OTH AF: 0.337

Alfa AF: 0.359 Hom.: 1737

Bravo AF: 0.316

Asia WGS AF: 0.439 AC: 1524 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.0
DANN	Benign	0.45

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: rs7523855; hg19: chr1-21840886;