rs188689330

chr1-21568199-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_000478.6(ALPL):c.744C>T(p.Asp248=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,614,034 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00050 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: ALPL NM_000478.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.06

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 1-21568199-C-T is Benign according to our data. Variant chr1-21568199-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.06 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6	c.744C>T	p.Asp248=	synonymous_variant	7/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.744C>T	p.Asp248=	synonymous_variant	7/12	1	NM_000478.6	P1
ALPL	ENST00000374832.5	c.744C>T	p.Asp248=	synonymous_variant	7/12	2		P1
ALPL	ENST00000540617.5	c.579C>T	p.Asp193=	synonymous_variant	6/11	2
ALPL	ENST00000539907.5	c.513C>T	p.Asp171=	synonymous_variant	5/10	2

Frequencies

GnomAD3 genomes AF: 0.000500 AC: 76 AN: 152038 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000231 AC: 58 AN: 251386 Hom.: 0 AF XY: 0.000213 AC XY: 29 AN XY: 135912

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000155 AC: 227 AN: 1461878 Hom.: 1 Cov.: 31 AF XY: 0.000160 AC XY: 116 AN XY: 727236

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000124

Gnomad4 OTH exome AF: 0.000546

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152156 Hom.: 1 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74374

Gnomad4 AFR AF: 0.000482

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000320 Hom.: 0

Bravo AF: 0.000548

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 11, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 20, 2019	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ALPL p.Asp171Asp variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs188689330) and ClinVar (classified as likely benign by Prevention Genetics). The variant was identified in control databases in 78 of 282744 chromosomes at a frequency of 0.000276 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 7 of 7222 chromosomes (freq: 0.000969), Latino in 29 of 35432 chromosomes (freq: 0.000819), African in 11 of 24944 chromosomes (freq: 0.000441) and European (non-Finnish) in 31 of 129096 chromosomes (freq: 0.00024), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The p.Asp171Asp variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	2.1
Dann	Benign	0.40

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: rs188689330; hg19: chr1-21894692; COSMIC: COSV66377290; COSMIC: COSV66377290;