rs387906941

chr14-50628157-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 PP5_Very_Strong

The NM_015915.5(ATL1):c.1246C>T(p.Arg416Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R416H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.23

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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_015915.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-50628158-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, ATL1
• PP5: Variant 14-50628157-C-T is Pathogenic according to our data. Variant chr14-50628157-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50628157-C-T is described in Lovd as [Pathogenic]. Variant chr14-50628157-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATL1	NM_015915.5	c.1246C>T	p.Arg416Cys	missense_variant	12/14	ENST00000358385.12
ATL1	NM_001127713.1	c.1246C>T	p.Arg416Cys	missense_variant	13/14
ATL1	NM_181598.4	c.1246C>T	p.Arg416Cys	missense_variant	12/13
ATL1	XM_047431430.1	c.1246C>T	p.Arg416Cys	missense_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATL1	ENST00000358385.12	c.1246C>T	p.Arg416Cys	missense_variant	12/14	1	NM_015915.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251296 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135794

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 3A Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Provincial Medical Genetics Program of British Columbia, University of British Columbia	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 15, 2023	For these reasons, this variant has been classified as Pathogenic. 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 not expected to disrupt ATL1 protein function. ClinVar contains an entry for this variant (Variation ID: 30582). This missense change has been observed in individuals with autosomal dominant hereditary spastic paraplegia (PMID: 21336785, 22581552, 29980238). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs387906941, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 416 of the ATL1 protein (p.Arg416Cys). -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2022

The c.1246C>T (p.R416C) alteration is located in exon 12 (coding exon 12) of the ATL1 gene. This alteration results from a C to T substitution at nucleotide position 1246, causing the arginine (R) at amino acid position 416 to be replaced by a cysteine (C). Based on the available evidence, the ATL1 c.1246C>T (p.R416C) alteration is classified as likely pathogenic for ATL1-related spastic paraplegia; however, its clinical significance for hereditary sensory neuropathy type ID is unclear. Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/251296) total alleles studied. The highest observed frequency was 0.005% (1/18386) of East Asian alleles. This variant has been detected in multiple individuals with hereditary spastic paraplegia in the heterozygous state (Lu, 2018; Zhao, 2019; Chen, 2019; Yan, 2019). In addition, this alteration was shown to segregate with disease in multiple individuals from three families who have clinical features consistent with hereditary spastic paraplegia (Orlacchio, 2011; Magariello, 2012; Luo, 2014). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, p.R416C is negligibly destabilizing to the ATL1 Middle domain and does not disrupt any known motifs or interaction interfaces (Byrnes, 2013; Kelly, 2021; Kelly, 2022). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

Hereditary spastic paraplegia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 17, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 20, 2022

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25341883, 29980238, 30780198, 28396731, 31227335, 31630374, 22581552, 21336785) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Uncertain	0.61
Sift	Benign	0.045	D;D
Sift4G	Uncertain	0.059	T;T
Polyphen		0.60	.;P
Vest4		0.76
MutPred		0.54		Loss of disorder (P = 0.0138);Loss of disorder (P = 0.0138);
MVP		0.93
MPC		0.91
ClinPred		0.58	D
GERP RS		4.9
Varity_R		0.51
gMVP		0.67

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: rs387906941; hg19: chr14-51094875; COSMIC: COSV63296295; COSMIC: COSV63296295;