1-21554125-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_000478.6(ALPL):c.44C>G(p.Thr15Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,590,560 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T15T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00023 (4 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.653

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 -14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000478.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.009112239).
• BP6: Variant 1-21554125-C-G is Benign according to our data. Variant chr1-21554125-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 740173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPL	NM_000478.6	c.44C>G	p.Thr15Ser	missense_variant	2/12	ENST00000374840.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPL	ENST00000374840.8	c.44C>G	p.Thr15Ser	missense_variant	2/12	1	NM_000478.6	P1

Frequencies

GnomAD3 genomes AF: 0.000113 AC: 17 AN: 150478 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000663

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00278

Gnomad FIN AF: 0.0000970

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000469 AC: 118 AN: 251480 Hom.: 2 AF XY: 0.000684 AC XY: 93 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00379

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000234 AC: 337 AN: 1439966 Hom.: 4 Cov.: 33 AF XY: 0.000323 AC XY: 231 AN XY: 716070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00369

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000100

Gnomad4 OTH exome AF: 0.000153

GnomAD4 genome AF: 0.000113 AC: 17 AN: 150594 Hom.: 0 Cov.: 31 AF XY: 0.000190 AC XY: 14 AN XY: 73612

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000661

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00278

Gnomad4 FIN AF: 0.0000970

Gnomad4 NFE AF: 0.0000296

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000576 AC: 70

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ALPL-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hypophosphatasia Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 22, 2019

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	7.9
Dann	Benign	0.82
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.53	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.0091	T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	-0.46	N;N
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.17	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.54	T;T
Sift4G	Benign	0.98	T;T
Polyphen		0.0010	B;B
Vest4		0.24
MutPred		0.46		Gain of disorder (P = 0.0692);Gain of disorder (P = 0.0692);
MVP		0.74
MPC		0.36
ClinPred		0.0092	T
GERP RS		2.5
Varity_R		0.037
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs150849772; hg19: chr1-21880618;