NM_015459.5:c.76C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_015459.5(ATL3):​c.76C>G​(p.Pro26Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P26P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ATL3
NM_015459.5 missense

Scores

2
8
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.88

Publications

0 publications found
Variant links:
Genes affected
ATL3 (HGNC:24526): (atlastin GTPase 3) This gene encodes a member of a family of dynamin-like, integral membrane GTPases. The encoded protein is required for the proper formation of the network of interconnected tubules of the endoplasmic reticulum. Mutations in this gene may be associated with hereditary sensory neuropathy type IF. Alternatively spliced transcript variants that encode distinct isoforms have been described. [provided by RefSeq, Feb 2014]
ATL3 Gene-Disease associations (from GenCC):
  • neuropathy, hereditary sensory, type 1F
    Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
  • hereditary sensory and autonomic neuropathy type 1
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2
High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATL3NM_015459.5 linkc.76C>G p.Pro26Ala missense_variant Exon 2 of 13 ENST00000398868.8 NP_056274.3 Q6DD88

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATL3ENST00000398868.8 linkc.76C>G p.Pro26Ala missense_variant Exon 2 of 13 1 NM_015459.5 ENSP00000381844.3 Q6DD88
ATL3ENST00000538786.1 linkc.22C>G p.Pro8Ala missense_variant Exon 2 of 13 2 ENSP00000437593.1 F5H6I7
ATL3ENST00000540699.1 linkc.232C>G p.Pro78Ala missense_variant Exon 3 of 4 3 ENSP00000441842.1 F5GWF8
ATL3ENST00000535789.1 linkn.643C>G non_coding_transcript_exon_variant Exon 3 of 3 4

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152070
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000801
AC:
2
AN:
249560
AF XY:
0.00000739
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1461886
Hom.:
0
Cov.:
31
AF XY:
0.0000151
AC XY:
11
AN XY:
727246
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000216
AC:
24
AN:
1112004
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152070
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74276
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41394
American (AMR)
AF:
0.00
AC:
0
AN:
15258
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10590
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68026
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000301
Hom.:
0
Bravo
AF:
0.0000151
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neuropathy, hereditary sensory, type 1F Uncertain:2
Sep 22, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 566349). This variant has not been reported in the literature in individuals affected with ATL3-related conditions. This variant is present in population databases (rs201256418, gnomAD 0.002%). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 26 of the ATL3 protein (p.Pro26Ala). 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. -

Nov 14, 2022
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Uncertain
0.051
T
BayesDel_noAF
Benign
-0.15
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.14
T;.;T
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.95
D;D;D
M_CAP
Benign
0.050
D
MetaRNN
Uncertain
0.52
D;D;D
MetaSVM
Benign
-0.57
T
MutationAssessor
Benign
0.97
L;.;.
PhyloP100
9.9
PrimateAI
Uncertain
0.56
T
PROVEAN
Pathogenic
-4.4
D;D;D
REVEL
Uncertain
0.29
Sift
Benign
0.070
T;T;T
Sift4G
Benign
0.13
T;T;.
Polyphen
0.38
B;.;D
Vest4
0.60
MutPred
0.34
Loss of glycosylation at P26 (P = 0.0426);.;.;
MVP
0.74
MPC
0.97
ClinPred
0.82
D
GERP RS
5.5
Varity_R
0.21
gMVP
0.55
Mutation Taster
=17/83
disease causing

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

Other links and lift over

dbSNP: rs201256418; hg19: chr11-63426695; API