rs1060502971
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP2PP5
The NM_015915.5(ATL1):c.461A>G(p.Gln154Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Q154E) has been classified as Uncertain significance.
Frequency
Consequence
NM_015915.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATL1 | NM_015915.5 | c.461A>G | p.Gln154Arg | missense_variant | 4/14 | ENST00000358385.12 | |
ATL1 | NM_001127713.1 | c.461A>G | p.Gln154Arg | missense_variant | 5/14 | ||
ATL1 | NM_181598.4 | c.461A>G | p.Gln154Arg | missense_variant | 4/13 | ||
ATL1 | XM_047431430.1 | c.461A>G | p.Gln154Arg | missense_variant | 5/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATL1 | ENST00000358385.12 | c.461A>G | p.Gln154Arg | missense_variant | 4/14 | 1 | NM_015915.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Abnormal pyramidal sign Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
Hereditary spastic paraplegia 3A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 03, 2020 | In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. However, a different missense substitution at this codon (p.Gln154Glu) is reported to be deleterious (PMID: 20932283). This indicates that the p.Gln154 residue is important for ATL1 protein function. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ATL1-related disease. This sequence change replaces glutamine with arginine at codon 154 of the ATL1 protein (p.Gln154Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at