chr1-21568212-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4
The NM_000478.6(ALPL):āc.757G>Cā(p.Val253Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V253I) has been classified as Uncertain significance.
Frequency
Consequence
NM_000478.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALPL | NM_000478.6 | c.757G>C | p.Val253Leu | missense_variant | 7/12 | ENST00000374840.8 | NP_000469.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALPL | ENST00000374840.8 | c.757G>C | p.Val253Leu | missense_variant | 7/12 | 1 | NM_000478.6 | ENSP00000363973.3 | ||
ALPL | ENST00000374832.5 | c.757G>C | p.Val253Leu | missense_variant | 7/12 | 2 | ENSP00000363965.1 | |||
ALPL | ENST00000540617.5 | c.592G>C | p.Val198Leu | missense_variant | 6/11 | 2 | ENSP00000442672.1 | |||
ALPL | ENST00000539907.5 | c.526G>C | p.Val176Leu | missense_variant | 5/10 | 2 | ENSP00000437674.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251356Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135902
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461860Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727224
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 22, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. This variant has not been reported in the literature in individuals affected with ALPL-related conditions. This variant is present in population databases (rs151270365, gnomAD 0.0009%). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 253 of the ALPL protein (p.Val253Leu). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at