1-21575943-G-T

Position:

• chr1-21575943-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000374840.8(ALPL):​c.1189+19G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.029 in 1,614,054 control chromosomes in the GnomAD database, including 800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (63 hom., cov: 32)
  • Exomes 𝑓: 0.030 (737 hom.)
• Consequence: ALPL ENST00000374840.8 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.364

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-21575943-G-T is Benign according to our data. Variant chr1-21575943-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 256226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21575943-G-T is described in Lovd as [Benign]. Variant chr1-21575943-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.021 (3204/152294) while in subpopulation NFE AF= 0.0348 (2369/68022). AF 95% confidence interval is 0.0337. There are 63 homozygotes in gnomad4. There are 1459 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 63 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALPL	NM_000478.6	c.1189+19G>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.1189+19G>T		intron_variant		1	NM_000478.6	ENSP00000363973	P1

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 3204 AN: 152176 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.00456

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0348

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.0218 AC: 5466 AN: 251306 Hom.: 93 AF XY: 0.0220 AC XY: 2993 AN XY: 135828

Gnomad AFR exome AF: 0.00535

Gnomad AMR exome AF: 0.00841

Gnomad ASJ exome AF: 0.0154

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00745

Gnomad FIN exome AF: 0.0300

Gnomad NFE exome AF: 0.0345

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0298 AC: 43591 AN: 1461760 Hom.: 737 Cov.: 32 AF XY: 0.0291 AC XY: 21177 AN XY: 727180

Gnomad4 AFR exome AF: 0.00397

Gnomad4 AMR exome AF: 0.00908

Gnomad4 ASJ exome AF: 0.0155

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00711

Gnomad4 FIN exome AF: 0.0313

Gnomad4 NFE exome AF: 0.0350

Gnomad4 OTH exome AF: 0.0239

GnomAD4 genome AF: 0.0210 AC: 3204 AN: 152294 Hom.: 63 Cov.: 32 AF XY: 0.0196 AC XY: 1459 AN XY: 74464

Gnomad4 AFR AF: 0.00455

Gnomad4 AMR AF: 0.00876

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.0261

Gnomad4 NFE AF: 0.0348

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0172 Hom.: 9

Bravo AF: 0.0201

Asia WGS AF: 0.00375 AC: 14 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	- -

Infantile hypophosphatasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Dec 19, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.3
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61778393; hg19: chr1-21902436; COSMIC: COSV66376200;