NM_000478.6:c.3G>C

Variant names:

• chr1-21554084-G-C
• NM_000478.6:c.3G>C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_000478.6(ALPL):​c.3G>C​(p.Met1?) variant causes a start lost 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ALPL NM_000478.6 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.16

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]

ENSG00000289715 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 48 pathogenic variants. Next in-frame start position is after 56 codons. Genomic position: 21560730. Lost 0.105 part of the original CDS.
• PS1: Another start lost variant in NM_000478.6 (ALPL) was described as [Likely_pathogenic] in ClinVar as 1382079
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-21554084-G-C is Pathogenic according to our data. Variant chr1-21554084-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 2700107.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPL	NM_000478.6	c.3G>C	p.Met1?	start_lost	Exon 2 of 12	ENST00000374840.8	NP_000469.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPL	ENST00000374840.8	c.3G>C	p.Met1?	start_lost	Exon 2 of 12	1	NM_000478.6	ENSP00000363973.3
ENSG00000289715	ENST00000696766.1	c.*82G>C		downstream_gene_variant				ENSP00000512858.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the ALPL mRNA. The next in-frame methionine is located at codon 56. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with hypophosphatasia (PMID: 21419245). It has also been observed to segregate with disease in related individuals. This variant disrupts a region of the ALPL protein in which other variant(s) (p.Ala33Val) have been determined to be pathogenic (PMID: 1409720, 15694177, 17253930, 22397652, 25731960). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	0.010
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.23	D
PROVEAN	Benign	-0.66	N;N
REVEL	Uncertain	0.53
Sift	Benign	0.040	D;D
Sift4G	Benign	0.25	T;T
Polyphen		0.0	B;B
Vest4		0.82
MutPred		0.88		Gain of catalytic residue at M1 (P = 0.0181);Gain of catalytic residue at M1 (P = 0.0181);
MVP		0.98
ClinPred		0.96	D
GERP RS		4.7
Varity_R		0.31
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-21880577;