rs397514712

Positions:

• chr14-50628155-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_015915.5(ATL1):​c.1244G>A​(p.Arg415Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R415W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 5.89

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-50628154-C-T 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATL1	NM_015915.5	c.1244G>A	p.Arg415Gln	missense_variant	12/14	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1	c.1244G>A	p.Arg415Gln	missense_variant	13/14		NP_001121185.1
ATL1	NM_181598.4	c.1244G>A	p.Arg415Gln	missense_variant	12/13		NP_853629.2
ATL1	XM_047431430.1	c.1244G>A	p.Arg415Gln	missense_variant	13/15		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12	c.1244G>A	p.Arg415Gln	missense_variant	12/14	1	NM_015915.5	ENSP00000351155.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251276 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135788

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727248

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 3A Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 20, 2021	This variant disrupts the p.Arg415 amino acid residue in ATL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15184642, 16401858, 19459885, 20932283, 23483706, 24417445, 24451228, 26671083). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 56844). This missense change has been observed in individual(s) with autosomal dominant and autosomal recessive hereditary spastic paraplegia (PMID: 23483706). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 415 of the ATL1 protein (p.Arg415Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2013	- -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 28, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one family with clinical features associated with this gene. This variant was identified in the heterozygous state in both affected and asymptomatic members of the family. This variant was also identified in the homozygous state in other affected members of the family. Computational tools disagree on the variant's effect on normal protein function. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2017	The R415Q variant in the ATL1 gene has been reported previously in multiple individuals in a family affected with hereditary spastic paraplegia in both the homozygous and heterozygous state (Varga et al., 2013). The R415Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R415Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The R415Q variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.086
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.88	L;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.090	N;N
REVEL	Uncertain	0.43
Sift	Benign	0.57	T;T
Sift4G	Benign	0.73	T;T
Polyphen		0.012	.;B
Vest4		0.74
MutPred		0.45		Loss of MoRF binding (P = 0.0446);Loss of MoRF binding (P = 0.0446);
MVP		0.92
MPC		0.76
ClinPred		0.62	D
GERP RS		4.9
Varity_R		0.46
gMVP		0.63

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: rs397514712; hg19: chr14-51094873; COSMIC: COSV104417950; COSMIC: COSV104417950;