14-50614406-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3PP5

The NM_015915.5(ATL1):​c.757G>T​(p.Val253Phe) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V253I) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ATL1
NM_015915.5 missense

Scores

9
9
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 10.0

Publications

0 publications found
Variant links:
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]
ATL1 Gene-Disease associations (from GenCC):
  • hereditary spastic paraplegia 3A
    Inheritance: AD, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
  • neuropathy, hereditary sensory, type 1D
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
  • hereditary sensory and autonomic neuropathy type 1
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 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, 7 uncertain in NM_015915.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr14-50614406-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 220424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in the ATL1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 60 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 2.6313 (below the threshold of 3.09). Trascript score misZ: 3.8383 (above the threshold of 3.09). GenCC associations: The gene is linked to hereditary spastic paraplegia 3A, neuropathy, hereditary sensory, type 1D, hereditary sensory and autonomic neuropathy type 1.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.809
PP5
Variant 14-50614406-G-T is Pathogenic according to our data. Variant chr14-50614406-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2504269.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATL1NM_015915.5 linkc.757G>T p.Val253Phe missense_variant Exon 8 of 14 ENST00000358385.12 NP_056999.2 Q8WXF7-1A0A0S2Z5B0Q53F53
ATL1NM_001127713.1 linkc.757G>T p.Val253Phe missense_variant Exon 9 of 14 NP_001121185.1 Q8WXF7-2A0A0S2Z5A2Q53F53
ATL1NM_181598.4 linkc.757G>T p.Val253Phe missense_variant Exon 8 of 13 NP_853629.2 Q8WXF7-2A0A0S2Z5A2Q53F53
ATL1XM_047431430.1 linkc.757G>T p.Val253Phe missense_variant Exon 9 of 15 XP_047287386.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATL1ENST00000358385.12 linkc.757G>T p.Val253Phe missense_variant Exon 8 of 14 1 NM_015915.5 ENSP00000351155.7 Q8WXF7-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Jun 12, 2025
GeneDx
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23334294, 35578252, 31594988, 26208798, 15596607) -

Hereditary spastic paraplegia 3A Uncertain:1
Sep 06, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. This variant disrupts the p.Val253 amino acid residue in ATL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15596607, 16401858, 17285536, 20932283, 24604904, 26208798). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 ATL1 protein function. ClinVar contains an entry for this variant (Variation ID: 2504269). This variant has not been reported in the literature in individuals affected with ATL1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 253 of the ATL1 protein (p.Val253Phe). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.59
.;D
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Uncertain
0.096
D
MetaRNN
Pathogenic
0.81
D;D
MetaSVM
Uncertain
-0.091
T
MutationAssessor
Uncertain
2.7
M;M
PhyloP100
10
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-2.9
D;D
REVEL
Uncertain
0.51
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.0040
D;D
Polyphen
1.0
.;D
Vest4
0.81
MutPred
0.57
Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);
MVP
0.77
MPC
1.9
ClinPred
0.97
D
GERP RS
5.6
Varity_R
0.91
gMVP
0.92
Mutation Taster
=1/99
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs864622520; hg19: chr14-51081124; API