rs201256418

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -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 (★).

Frequency

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

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ATL3
NM_015459.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.88

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 Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATL3	NM_015459.5 link	c.76C>G	p.Pro26Ala	missense_variant	Exon 2 of 13	ENST00000398868.8	NP_056274.3	Q6DD88
ATL3	NM_001290048.2 link	c.22C>G	p.Pro8Ala	missense_variant	Exon 2 of 13		NP_001276977.1	Q6DD88F5H6I7B4DXC4
ATL3	XM_047426725.1 link	c.232C>G	p.Pro78Ala	missense_variant	Exon 3 of 14		XP_047282681.1
ATL3	XM_006718493.2 link	c.76C>G	p.Pro26Ala	missense_variant	Exon 2 of 12		XP_006718556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATL3	ENST00000398868.8 link	c.76C>G	p.Pro26Ala	missense_variant	Exon 2 of 13	1	NM_015459.5	ENSP00000381844.3	Q6DD88
ATL3	ENST00000538786.1 link	c.22C>G	p.Pro8Ala	missense_variant	Exon 2 of 13	2		ENSP00000437593.1	F5H6I7
ATL3	ENST00000540699.1 link	c.232C>G	p.Pro78Ala	missense_variant	Exon 3 of 4	3		ENSP00000441842.1	F5GWF8
ATL3	ENST00000535789.1 link	n.643C>G		non_coding_transcript_exon_variant	Exon 3 of 3	4

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152070

Hom.:

Cov.:

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

GnomAD3 exomes

AF:

0.00000801

AC:

AN:

249560

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135398

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 SAS 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:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000301

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

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

Nov 14, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.051

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;.;T

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.050

MetaRNN

Uncertain

0.52

D;D;D

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.97

L;.;.

PrimateAI

Uncertain

0.56

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

GERP RS

5.5

Varity_R

0.21

gMVP

0.55

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.

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