rs1186954818
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3
The NM_015915.5(ATL1):āc.769A>Gā(p.Ile257Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.0000041 ( 0 hom. )
Consequence
ATL1
NM_015915.5 missense
NM_015915.5 missense
Scores
3
12
3
Clinical Significance
Conservation
PhyloP100: 9.26
Genes affected
ATL1 (HGNC:11231): (atlastin GTPase 1) The protein encoded by this gene is a GTPase and a Golgi body transmembrane protein. The encoded protein can form a homotetramer and has been shown to interact with spastin and with mitogen-activated protein kinase kinase kinase kinase 4. This protein may be involved in axonal maintenance as evidenced by the fact that defects in this gene are a cause of spastic paraplegia type 3. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_015915.5
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, ATL1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.796
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATL1 | NM_015915.5 | c.769A>G | p.Ile257Val | missense_variant | 8/14 | ENST00000358385.12 | |
ATL1 | NM_001127713.1 | c.769A>G | p.Ile257Val | missense_variant | 9/14 | ||
ATL1 | NM_181598.4 | c.769A>G | p.Ile257Val | missense_variant | 8/13 | ||
ATL1 | XM_047431430.1 | c.769A>G | p.Ile257Val | missense_variant | 9/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATL1 | ENST00000358385.12 | c.769A>G | p.Ile257Val | missense_variant | 8/14 | 1 | NM_015915.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461740Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727178
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74368
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 3A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 26, 2019 | 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. 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 C25"). This variant has not been reported in the literature in individuals with ATL1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with valine at codon 257 of the ATL1 protein (p.Ile257Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
0.55
.;P
Vest4
MutPred
Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);
MVP
MPC
0.67
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at