rs28939094

Positions:

• chr14-50628133-A-G
• chr14-50628133-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_015915.5(ATL1):​c.1222A>G​(p.Met408Val) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M408T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 U:1 O:1
• Conservation: PhyloP100: 9.32

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]

ATL1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-50628134-T-C is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATL1. . Gene score misZ 2.6313 (greater than the threshold 3.09). Trascript score misZ 3.8383 (greater than threshold 3.09). GenCC has associacion of gene with hereditary sensory and autonomic neuropathy type 1, hereditary spastic paraplegia 3A, neuropathy, hereditary sensory, type 1D.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 14-50628133-A-G is Pathogenic according to our data. Variant chr14-50628133-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 4351.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-50628133-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATL1	NM_015915.5	c.1222A>G	p.Met408Val	missense_variant	12/14	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1	c.1222A>G	p.Met408Val	missense_variant	13/14		NP_001121185.1
ATL1	NM_181598.4	c.1222A>G	p.Met408Val	missense_variant	12/13		NP_853629.2
ATL1	XM_047431430.1	c.1222A>G	p.Met408Val	missense_variant	13/15		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12	c.1222A>G	p.Met408Val	missense_variant	12/14	1	NM_015915.5	ENSP00000351155.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 3A Pathogenic:2 Uncertain:1 Other:1

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 23, 2022	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 408 of the ATL1 protein (p.Met408Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant hereditary spastic paraplegia (PMID: 12939451). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4351). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATL1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Met408 amino acid residue in ATL1. Other variant(s) that disrupt this residue have been observed in individuals with ATL1-related conditions (PMID: 12939451, 17502470), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 26, 2003	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	.;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.88	.;P
Vest4		0.90
MutPred		0.90		Gain of methylation at K407 (P = 0.0172);Gain of methylation at K407 (P = 0.0172);
MVP		0.94
MPC		1.2
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.92
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs28939094; hg19: chr14-51094851;