rs183951324

Positions:

chr11-63631057-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_015459.5(ATL3):c.1522G>A(p.Ala508Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000416 in 1,611,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

ATL3
NM_015459.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.68

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03883028).

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATL3	NM_015459.5 linkuse as main transcript	c.1522G>A	p.Ala508Thr	missense_variant	12/13	ENST00000398868.8	NP_056274.3	Q6DD88
ATL3	NM_001290048.2 linkuse as main transcript	c.1468G>A	p.Ala490Thr	missense_variant	12/13		NP_001276977.1	Q6DD88F5H6I7B4DXC4
ATL3	XM_047426725.1 linkuse as main transcript	c.1678G>A	p.Ala560Thr	missense_variant	13/14		XP_047282681.1
ATL3	XM_006718493.2 linkuse as main transcript	c.1465G>A	p.Ala489Thr	missense_variant	11/12		XP_006718556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATL3	ENST00000398868.8 linkuse as main transcript	c.1522G>A	p.Ala508Thr	missense_variant	12/13	1	NM_015459.5	ENSP00000381844.3		Q6DD88
ATL3	ENST00000538786.1 linkuse as main transcript	c.1468G>A	p.Ala490Thr	missense_variant	12/13	2		ENSP00000437593.1		F5H6I7

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

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:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.0000283

AC:

AN:

246936

Hom.:

AF XY:

0.00000747

AC XY:

AN XY:

133898

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000582

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000295

AC:

AN:

1459174

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

725760

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000247

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000996

GnomAD4 genome

AF:

0.000158

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000412

ESP6500AA

AF:

0.000244

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 03, 2023

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 541688). This variant has not been reported in the literature in individuals affected with ATL3-related conditions. This variant is present in population databases (rs183951324, gnomAD 0.009%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 508 of the ATL3 protein (p.Ala508Thr). 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. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2023

The c.1522G>A (p.A508T) alteration is located in exon 12 (coding exon 12) of the ATL3 gene. This alteration results from a G to A substitution at nucleotide position 1522, causing the alanine (A) at amino acid position 508 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.0052

T;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.076

MetaRNN

Benign

0.039

T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.86

L;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.32

N;N

REVEL

Benign

0.14

Sift

Benign

0.49

T;T

Sift4G

Benign

0.53

T;T

Polyphen

0.0040

B;.

Vest4

0.087

MVP

0.93

MPC

0.28

ClinPred

0.047

GERP RS

3.4

Varity_R

0.018

gMVP

0.12

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over