14-50591009-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_015915.5(ATL1):​c.351G>C​(p.Glu117Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E117E) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ATL1
NM_015915.5 missense

Scores

8
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.37
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a domain GB1/RHD3-type G (size 245) in uniprot entity ATLA1_HUMAN there are 38 pathogenic changes around while only 0 benign (100%) in NM_015915.5
PM2
Very rare variant in population databases, with high coverage;
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 sensory and autonomic neuropathy type 1, hereditary spastic paraplegia 3A, neuropathy, hereditary sensory, type 1D.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATL1NM_015915.5 linkc.351G>C p.Glu117Asp missense_variant Exon 3 of 14 ENST00000358385.12 NP_056999.2 Q8WXF7-1A0A0S2Z5B0Q53F53
ATL1NM_001127713.1 linkc.351G>C p.Glu117Asp missense_variant Exon 4 of 14 NP_001121185.1 Q8WXF7-2A0A0S2Z5A2Q53F53
ATL1NM_181598.4 linkc.351G>C p.Glu117Asp missense_variant Exon 3 of 13 NP_853629.2 Q8WXF7-2A0A0S2Z5A2Q53F53
ATL1XM_047431430.1 linkc.351G>C p.Glu117Asp missense_variant Exon 4 of 15 XP_047287386.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATL1ENST00000358385.12 linkc.351G>C p.Glu117Asp missense_variant Exon 3 of 14 1 NM_015915.5 ENSP00000351155.7 Q8WXF7-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
43
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.45
BayesDel_addAF
Uncertain
0.058
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.35
.;T;.
Eigen
Benign
-0.51
Eigen_PC
Benign
-0.32
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Benign
0.027
D
MetaRNN
Uncertain
0.50
T;T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Benign
1.9
L;L;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-1.5
N;N;N
REVEL
Uncertain
0.33
Sift
Benign
0.19
T;T;T
Sift4G
Benign
0.15
T;T;T
Polyphen
0.0040
.;B;.
Vest4
0.28
MutPred
0.54
Loss of disorder (P = 0.1558);Loss of disorder (P = 0.1558);.;
MVP
0.89
MPC
0.61
ClinPred
0.43
T
GERP RS
3.4
Varity_R
0.52
gMVP
0.62

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1060197; hg19: chr14-51057727; API