Variant 11-63643411-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The ENST00000398868.8(ATL3):c.796C>A(p.Pro266Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ATL3
ENST00000398868.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

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:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ATL3	NM_015459.5 linkuse as main transcript	c.796C>A	p.Pro266Thr	missense_variant	8/13	ENST00000398868.8	NP_056274.3
ATL3	NM_001290048.2 linkuse as main transcript	c.742C>A	p.Pro248Thr	missense_variant	8/13		NP_001276977.1
ATL3	XM_047426725.1 linkuse as main transcript	c.952C>A	p.Pro318Thr	missense_variant	9/14		XP_047282681.1
ATL3	XM_006718493.2 linkuse as main transcript	c.739C>A	p.Pro247Thr	missense_variant	7/12		XP_006718556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ATL3	ENST00000398868.8 linkuse as main transcript	c.796C>A	p.Pro266Thr	missense_variant	8/13	1	NM_015459.5	ENSP00000381844
	ENST00000540307.1 linkuse as main transcript	n.59+5676G>T		intron_variant, non_coding_transcript_variant		3
ATL3	ENST00000538786.1 linkuse as main transcript	c.742C>A	p.Pro248Thr	missense_variant	8/13	2		ENSP00000437593	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1458952

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725718

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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

Jan 27, 2020

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ATL3-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with threonine at codon 266 of the ATL3 protein (p.Pro266Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.090

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.40

MutationAssessor

Pathogenic

3.4

M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-7.2

D;D

REVEL

Pathogenic

0.81

Sift

Benign

0.032

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.97

MutPred

0.83

Gain of sheet (P = 0.0344);.;

MVP

0.97

MPC

1.1

ClinPred

1.0

GERP RS

5.4

Varity_R

0.92

gMVP

0.76

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