chr1-21563146-G-A

Position:

• chr1-21563146-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000478.6(ALPL):​c.334G>A​(p.Gly112Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000089 in 1,461,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G112A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 6.79

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000478.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-21563147-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1064140.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 1-21563146-G-A is Pathogenic according to our data. Variant chr1-21563146-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 549969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-21563146-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALPL	NM_000478.6	c.334G>A	p.Gly112Ser	missense_variant	5/12	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8	c.334G>A	p.Gly112Ser	missense_variant	5/12	1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461424 Hom.: 0 Cov.: 37 AF XY: 0.00000825 AC XY: 6 AN XY: 727044

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 112 of the ALPL protein (p.Gly112Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 15300736, 27312557, 28127875, 32160374). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Gly95Ser. ClinVar contains an entry for this variant (Variation ID: 549969). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ALPL protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Childhood hypophosphatasia;C0268412:Infantile hypophosphatasia;C0268413:Adult hypophosphatasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 04, 2024

- -

Adult hypophosphatasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 13, 2024

- -

Infantile hypophosphatasia Uncertain:1

Uncertain significance, flagged submission

clinical testing

Counsyl

Dec 21, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;D;D;T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	0.93	L;.;.;L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Pathogenic	0.76
Sift	Benign	0.16	T;T;T;T
Sift4G	Benign	0.29	T;T;T;T
Polyphen		1.0	D;.;.;D
Vest4		0.80
MutPred		0.86		Gain of glycosylation at G112 (P = 0.0507);.;.;Gain of glycosylation at G112 (P = 0.0507);
MVP		0.97
MPC		1.2
ClinPred		0.98	D
GERP RS		3.6
Varity_R		0.26
gMVP		0.95

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: rs1384701659; hg19: chr1-21889639;