11-63631201-G-A

Variant names:

• chr11-63631201-G-A
• rs1463846374
• NM_015459.5:c.1378C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015459.5(ATL3):​c.1378C>T​(p.Leu460Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L460V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATL3 NM_015459.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.129
• Publications: 0 publications found

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

ENSG00000256789 (HGNC:58146):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15755111).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL3	NM_015459.5	MANE Select	c.1378C>T	p.Leu460Phe	missense	Exon 12 of 13	NP_056274.3
	ATL3	NM_001440716.1		c.1327C>T	p.Leu443Phe	missense	Exon 11 of 12	NP_001427645.1
	ATL3	NM_001290048.2		c.1324C>T	p.Leu442Phe	missense	Exon 12 of 13	NP_001276977.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL3	ENST00000398868.8	TSL:1 MANE Select	c.1378C>T	p.Leu460Phe	missense	Exon 12 of 13	ENSP00000381844.3
	ATL3	ENST00000538786.1	TSL:2	c.1324C>T	p.Leu442Phe	missense	Exon 12 of 13	ENSP00000437593.1
	ENSG00000256789	ENST00000540307.2	TSL:3	n.121-6290G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuropathy, hereditary sensory, type 1F Uncertain:1

Apr 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The phenylalanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 460 of the ATL3 protein (p.Leu460Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.52	N
PhyloP100		-0.13
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.16
Sift	Benign	0.39	T
Sift4G	Benign	0.40	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.29		Loss of helix (P = 0.0558)
MVP		0.92
MPC		0.32
ClinPred		0.13	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.028
gMVP		0.34
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs1463846374; hg19: chr11-63398673;