rs119476050

Positions:

• chr14-50628154-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_015915.5(ATL1):​c.1243C>T​(p.Arg415Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R415Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 U:1 O:1
• Conservation: PhyloP100: 3.25

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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-50628155-G-A 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, 0.919
• PP5: Variant 14-50628154-C-T is Pathogenic according to our data. Variant chr14-50628154-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50628154-C-T is described in Lovd as [Pathogenic]. Variant chr14-50628154-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATL1	NM_015915.5	c.1243C>T	p.Arg415Trp	missense_variant	12/14	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1	c.1243C>T	p.Arg415Trp	missense_variant	13/14		NP_001121185.1
ATL1	NM_181598.4	c.1243C>T	p.Arg415Trp	missense_variant	12/13		NP_853629.2
ATL1	XM_047431430.1	c.1243C>T	p.Arg415Trp	missense_variant	13/15		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12	c.1243C>T	p.Arg415Trp	missense_variant	12/14	1	NM_015915.5	ENSP00000351155.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251278 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135786

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 0.00000205 AC: 3 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 3A Pathogenic:5 Uncertain:1 Other:1

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 415 of the ATL1 protein (p.Arg415Trp). This variant is present in population databases (rs119476050, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant hereditary spastic paraplegia (PMID: 15184642, 16401858, 19459885, 20932283, 23483706, 24417445, 24451228). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4352). 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 with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2013	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.1243C>Tp.Arg415Trp in ATL1 gene has been reported in heterozygous state in multiple individuals with hereditary spastic paraplegia Yan YT, et al., 2019, Elert-Dobkowska E, et al., 2015. This variant is located in a mutational hotspot. A different variant p.Arg415Gln has been reported in a Chinese patient with hereditary spastic paraplegia Xiao XW, et al., 2019. The variant is reported with 0.0004% allele frequency in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. However, experimental studies on the pathogenicity of the variant are not available.The amino acid Arginine at position 415 is changed to a Tryptophan changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Arg415Trp in ATL1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 29, 2023	- -

not provided Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 10, 2020	PS4_moderate, PM1, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ATL1: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 29, 2024	The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with clinical features associated with autosomal dominant spastic paraplegia. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2024	Reported previously in a large multi-generation family with early onset progressive spastic paraplegia in affected and unaffected individuals suggesting autosomal dominant inheritance with reduced penetrance (PMID: 15184642); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23334294, 24417445, 20862796, 21220294, 34808209, 20932283, 25341883, 31236401, 15184642, 26671083, 30780198, 19459885, 34983064, 16401858, 27108959, 24451228, 27217339, 37152446, 31594988, 4684346, Tolmacheva2023[preprint], 23483706) -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2014

The c.1243C>T (p.R415W) 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 1243, causing the arginine (R) at amino acid position 415 to be replaced by a tryptophan (W). Based on data from the NHLBI Exome Sequencing Project (ESP), the c.1243C>T alteration was not observed among 6,503 individuals tested (0.0%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. This alteration is currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP) under rs119476050. Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). The R415W missense alteration has been reported in several HSP families. The first report is an Italian family with pure autosomal dominant HSP (D'Amico, 2004). The proband was a 22-year old woman with slowly progressive HSP starting at age 3. Her brother and a maternal second cousin had a similar phenotype, while a maternal uncle and maternal great-uncle had infantile onset spastic paraparesis. The alteration was present in all affected individuals but was also present in nine unaffected relatives, who had normal neurological evaluations and motor evoked potentials (age range was 13-70 years). It was absent in 400 control chromosomes. This alteration was concluded to be a likely low penetrance mutation affected by modulator genes or strong epigenetic factors, although a neutral polymorphism could not be ruled out. This alteration was subsequently identified in second large family with apparently X-linked pure HSP. The alteration was present in three affected males and three unaffected family members, consistent with incomplete penetrance. Two of the unaffected carriers were women, and family history indicated that most unaffected women were obligate carriers. These findings were consistent with sex-associated reduced penetrance of this mutation. Varga et al. (2013) identified the same mutation in 1 of 83 Spanish patients with apparent sporadic HSP and in 2 of 28 Russian patients with dominant HSP. Evidence again suggested incomplete penetrance in these families._x000D_ _x000D_ A missense alteration affecting the same amino acid, R415Q, was reported in a consanguinous Moroccan family with childhood onset HSP (Varga, 2013). All four affected individuals were in the same generation, raising suspicion for an autosomal recessive etiology. Three of the affected individuals were found to be homozygous for the R415Q alteration and the fourth was heterozygous (three unaffected siblings and the parents were also heterozygous). The alteration showed complete penetrance in the homozygous state and incomplete penetrance in the heterozygous state. The authors discuss that c.1243C>T occurs at a CpG nucleotide and thus may represent a mutation hotspot. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	.;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.030	D;D
Polyphen		1.0	.;D
Vest4		0.85
MutPred		0.79		Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);
MVP		0.98
MPC		1.4
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.52
gMVP		0.74

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: rs119476050; hg19: chr14-51094872;