chr11-63646544-C-T

Position:

chr11-63646544-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2

The ENST00000398868.8(ATL3):c.581G>A(p.Arg194His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000068 in 1,604,046 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R194C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

ATL3
ENST00000398868.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 7.86

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.887

BP6

Variant 11-63646544-C-T is Benign according to our data. Variant chr11-63646544-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541677.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ATL3	NM_015459.5 linkuse as main transcript	c.581G>A	p.Arg194His	missense_variant	6/13	ENST00000398868.8	NP_056274.3
ATL3	NM_001290048.2 linkuse as main transcript	c.527G>A	p.Arg176His	missense_variant	6/13		NP_001276977.1
ATL3	XM_047426725.1 linkuse as main transcript	c.737G>A	p.Arg246His	missense_variant	7/14		XP_047282681.1
ATL3	XM_006718493.2 linkuse as main transcript	c.562-2283G>A		intron_variant			XP_006718556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ATL3	ENST00000398868.8 linkuse as main transcript	c.581G>A	p.Arg194His	missense_variant	6/13	1	NM_015459.5	ENSP00000381844
	ENST00000540307.1 linkuse as main transcript	n.60-4016C>T		intron_variant, non_coding_transcript_variant		3
ATL3	ENST00000538786.1 linkuse as main transcript	c.527G>A	p.Arg176His	missense_variant	6/13	2		ENSP00000437593	P1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000574

AC:

AN:

243848

Hom.:

AF XY:

0.0000681

AC XY:

AN XY:

132240

show subpopulations

Gnomad AFR exome

AF:

0.0000651

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000347

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000675

AC:

AN:

1451932

Hom.:

Cov.:

AF XY:

0.0000665

AC XY:

AN XY:

722310

show subpopulations

Gnomad4 AFR exome

AF:

0.0000608

Gnomad4 AMR exome

AF:

0.0000231

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000237

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000795

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000745

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

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 18, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 194 of the ATL3 protein (p.Arg194His). This variant is present in population databases (rs750850786, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of ATL3-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 541677). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATL3 protein function with a positive predictive value of 80%. 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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.54

D;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Uncertain

0.28

MutationAssessor

Pathogenic

3.8

H;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.016

D;D

Polyphen

1.0

D;.

Vest4

0.78

MVP

0.92

MPC

1.1

ClinPred

1.0

GERP RS

4.6

Varity_R

0.64

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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