chr14-50614406-G-A
Variant summary
Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PM5PP2PP5_Very_Strong
The NM_015915.5(ATL1):c.757G>A(p.Val253Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,744 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V253F) has been classified as Likely pathogenic.
Frequency
Consequence
NM_015915.5 missense
Scores
Clinical Significance
Conservation
Publications
- hereditary spastic paraplegia 3AInheritance: AD, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
- neuropathy, hereditary sensory, type 1DInheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
- hereditary sensory and autonomic neuropathy type 1Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATL1 | NM_015915.5 | c.757G>A | p.Val253Ile | missense_variant | Exon 8 of 14 | ENST00000358385.12 | NP_056999.2 | |
ATL1 | NM_001127713.1 | c.757G>A | p.Val253Ile | missense_variant | Exon 9 of 14 | NP_001121185.1 | ||
ATL1 | NM_181598.4 | c.757G>A | p.Val253Ile | missense_variant | Exon 8 of 13 | NP_853629.2 | ||
ATL1 | XM_047431430.1 | c.757G>A | p.Val253Ile | missense_variant | Exon 9 of 15 | XP_047287386.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461744Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727180 show subpopulations
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:5
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PP1, PP4, PM1, PM2_moderate, PS4 -
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ATL1: PM1, PM2, PS4:Moderate -
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20932283, 26208798, 15596607, 34782662, 17285536, 34015694, 20718791, 16401858, 31236401, 23334294, 21194679, 36359747, 35578252, 24604904, 31594988, 27751653, 34983064, 32277485) -
Hereditary spastic paraplegia 3A Pathogenic:2Uncertain:1
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This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 253 of the ATL1 protein (p.Val253Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant hereditary spastic paraplegia (PMID: 15596607, 16401858, 17285536, 20932283, 24604904, 26208798). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 220424). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATL1 protein function. For these reasons, this variant has been classified as Pathogenic. -
Hereditary spastic paraplegia Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at