11-63631157-G-C

Variant names:

• chr11-63631157-G-C
• rs1057522704
• NM_015459.5:c.1422C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015459.5(ATL3):​c.1422C>G​(p.Asn474Lys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATL3 NM_015459.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.60
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATL3	NM_015459.5	c.1422C>G	p.Asn474Lys	missense_variant	Exon 12 of 13	ENST00000398868.8	NP_056274.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATL3	ENST00000398868.8	c.1422C>G	p.Asn474Lys	missense_variant	Exon 12 of 13	1	NM_015459.5	ENSP00000381844.3
ATL3	ENST00000538786.1	c.1368C>G	p.Asn456Lys	missense_variant	Exon 12 of 13	2		ENSP00000437593.1
ENSG00000256789	ENST00000540307.2	n.121-6334G>C		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuropathy, hereditary sensory, type 1F Uncertain:1

Nov 30, 2018

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with ATL3-related disease. ClinVar contains an entry for this variant (Variation ID: 387129). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with lysine at codon 474 of the ATL3 protein (p.Asn474Lys). The asparagine residue is moderately conserved and there is a moderate physicochemical difference between asparagine and lysine. -

not provided Uncertain:1

Jun 17, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The N474K variant in the ATL3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The N474K variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N474K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret N474K as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.8	M;.
PhyloP100		2.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.72
Sift	Benign	0.045	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.97	D;.
Vest4		0.83
MutPred		0.58		Gain of methylation at N474 (P = 0.0078);.;
MVP		0.98
MPC		0.56
ClinPred		0.99	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.53
Mutation Taster		=61/39	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: rs1057522704; hg19: chr11-63398629;