1-21575879-G-C

Variant names:

• chr1-21575879-G-C
• rs771540767
• NM_000478.6:c.1144G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_000478.6(ALPL):​c.1144G>C​(p.Val382Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V382I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.69
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• adult hypophosphatasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
• childhood hypophosphatasia

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, ClinGen, Orphanet
• hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, G2P
• infantile hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia
• odontohypophosphatasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• perinatal lethal hypophosphatasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr1-21575879-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 371163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 220 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 1.2672 (below the threshold of 3.09). Trascript score misZ: 1.9021 (below the threshold of 3.09). GenCC associations: The gene is linked to adult hypophosphatasia, infantile hypophosphatasia, odontohypophosphatasia, childhood hypophosphatasia, hypophosphatasia, perinatal lethal hypophosphatasia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 1-21575879-G-C is Pathogenic according to our data. Variant chr1-21575879-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2775415.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6	c.1144G>C	p.Val382Leu	missense_variant	Exon 10 of 12	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8	c.1144G>C	p.Val382Leu	missense_variant	Exon 10 of 12	1	NM_000478.6	ENSP00000363973.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypophosphatasia Pathogenic:1

Sep 19, 2023

MVZ Dr. Eberhard & Partner Dortmund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was not found in control groups of different ethnicities and has not been mentioned in the literature so far. Computer-based analyses consistently show that p.(Val382Leu) influences the function of the protein and could be pathogenetically significant. Contrary to the nucleotide (moderately conserved), the affected amino acid is highly conserved. The pathogenic missense variant for p.(Val382Ile) has been described at the same codon and is thought to be pathogenic due to a dominant negative effect (functional study showed no residual activity for p.(Val382Ile) (PMID: 12412800)). The region surrounding the affected nucleotide position also shows several pathogenic or likely pathogenic missense/in frame variants but no benign variants. -

not specified Uncertain:1

May 21, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ALPL c.1144G>C (p.Val382Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251488 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1144G>C in individuals affected with Hypophosphatasia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2775415). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;D
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	2.9	M;.;.;M
PhyloP100		5.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.019	D;D;D;D
Sift4G	Uncertain	0.051	T;D;D;T
Polyphen		0.064	B;.;.;B
Vest4		0.66
MutPred		0.85		Loss of sheet (P = 0.1907);.;.;Loss of sheet (P = 0.1907);
MVP		0.98
MPC		0.46
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.63
gMVP		0.88
Mutation Taster		=38/62	disease causing

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

Other links and lift over

dbSNP: rs771540767; hg19: chr1-21902372;