rs1555365871

Variant names:

• chr14-50628290-T-A
• rs1555365871
• NM_015915.5:c.1379T>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_015915.5(ATL1):​c.1379T>A​(p.Val460Glu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.99

Genes affected

ATL1 (HGNC:11231): (atlastin GTPase 1) The protein encoded by this gene is a GTPase and a Golgi body transmembrane protein. The encoded protein can form a homotetramer and has been shown to interact with spastin and with mitogen-activated protein kinase kinase kinase kinase 4. This protein may be involved in axonal maintenance as evidenced by the fact that defects in this gene are a cause of spastic paraplegia type 3. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ATL1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 60 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 2.6313 (below the threshold of 3.09). Trascript score misZ: 3.8383 (above the threshold of 3.09). GenCC associations: The gene is linked to hereditary sensory and autonomic neuropathy type 1, hereditary spastic paraplegia 3A, neuropathy, hereditary sensory, type 1D.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATL1	NM_015915.5	c.1379T>A	p.Val460Glu	missense_variant	Exon 12 of 14	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1	c.1379T>A	p.Val460Glu	missense_variant	Exon 13 of 14		NP_001121185.1
ATL1	NM_181598.4	c.1379T>A	p.Val460Glu	missense_variant	Exon 12 of 13		NP_853629.2
ATL1	XM_047431430.1	c.1379T>A	p.Val460Glu	missense_variant	Exon 13 of 15		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12	c.1379T>A	p.Val460Glu	missense_variant	Exon 12 of 14	1	NM_015915.5	ENSP00000351155.7

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

Hereditary spastic paraplegia 3A Uncertain:1

Apr 23, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine with glutamic acid at codon 460 of the ATL1 protein (p.Val460Glu). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glutamic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ATL1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	.;D
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L;L
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.97	.;D
Vest4		0.93
MutPred		0.57		Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);
MVP		0.98
MPC		1.8
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.89
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555365871; hg19: chr14-51095008;