Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_015459.5(ATL3):c.575A>G(p.Tyr192Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Y192Y) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

ATL3
NM_015459.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.97

Publications

23 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

ATL3 links:

ENSG00000256789 (HGNC:58146):

ENSG00000256789 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

PP5

Variant 11-63646550-T-C is Pathogenic according to our data. Variant chr11-63646550-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 97070.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015459.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATL3	NM_015459.5	MANE Select	c.575A>G	p.Tyr192Cys	missense	Exon 6 of 13	NP_056274.3
ATL3	NM_001440716.1		c.524A>G	p.Tyr175Cys	missense	Exon 5 of 12	NP_001427645.1
ATL3	NM_001290048.2		c.521A>G	p.Tyr174Cys	missense	Exon 6 of 13	NP_001276977.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATL3	ENST00000398868.8	TSL:1 MANE Select	c.575A>G	p.Tyr192Cys	missense	Exon 6 of 13	ENSP00000381844.3
ATL3	ENST00000538786.1	TSL:2	c.521A>G	p.Tyr174Cys	missense	Exon 6 of 13	ENSP00000437593.1
ENSG00000256789	ENST00000540307.2	TSL:3	n.366-4010T>C		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neuropathy, hereditary sensory, type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.17

MutationAssessor

Pathogenic

3.9

PhyloP100

8.0

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-8.5

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.95

MVP

0.90

MPC

1.1

ClinPred

1.0

GERP RS

5.5

Varity_R

0.94

gMVP

0.74

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

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

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rs587777108

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over