rs1553415041

Positions:

• chr1-21577406-T-A
• chr1-21577406-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000478.6(ALPL):​c.1333T>A​(p.Ser445Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S445P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.396

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]

ALPL (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000478.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-21577406-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 552418.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALPL	NM_000478.6	c.1333T>A	p.Ser445Thr	missense_variant	12/12	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8	c.1333T>A	p.Ser445Thr	missense_variant	12/12	1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypophosphatasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

JKU Lab, Dept of Paediatrics, Johannes Kepler University

Apr 19, 2022

This variant is absent from large population studies. REVEL score inconclusive (REVEL: 0.469). ACMG Criteria used for classification: PM2_sup, PP2_sup. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;.;.;D
Eigen	Benign	-0.023
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	.;T;T;T
M_CAP	Pathogenic	0.70	D
MetaRNN	Uncertain	0.57	D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.4	L;.;.;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.047	D;D;D;D
Sift4G	Benign	0.071	T;T;T;T
Polyphen		0.82	P;.;.;P
Vest4		0.38
MutPred		0.62		Loss of glycosylation at S445 (P = 0.0621);.;.;Loss of glycosylation at S445 (P = 0.0621);
MVP		0.96
MPC		0.86
ClinPred		0.87	D
GERP RS		4.6
Varity_R		0.17
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-21903899;