11-63631157-G-T

Variant names:

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

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>A​(p.Asn474Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATL3 NM_015459.5 missense
• Clinical Significance: Not reported in ClinVar
• 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, ClinGen, Labcorp Genetics (formerly Invitae)
• hereditary sensory and autonomic neuropathy type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LNCROPM (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, 0.831

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL3	NM_015459.5	MANE Select	c.1422C>A	p.Asn474Lys	missense	Exon 12 of 13	NP_056274.3
	ATL3	NM_001440716.1		c.1371C>A	p.Asn457Lys	missense	Exon 11 of 12	NP_001427645.1
	ATL3	NM_001290048.2		c.1368C>A	p.Asn456Lys	missense	Exon 12 of 13	NP_001276977.1	F5H6I7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL3	ENST00000398868.8	TSL:1 MANE Select	c.1422C>A	p.Asn474Lys	missense	Exon 12 of 13	ENSP00000381844.3	Q6DD88
	ATL3	ENST00000955365.1		c.1419C>A	p.Asn473Lys	missense	Exon 12 of 13	ENSP00000625424.1
	ATL3	ENST00000538786.1	TSL:2	c.1368C>A	p.Asn456Lys	missense	Exon 12 of 13	ENSP00000437593.1	F5H6I7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.72
Sift	Benign	0.045	D
Sift4G	Uncertain	0.012	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
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;