rs606231265

Positions:

• chr14-50591011-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The NM_015915.5(ATL1):​c.353G>A​(p.Arg118Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,260 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 6.79

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain GB1/RHD3-type G (size 245) in uniprot entity ATLA1_HUMAN there are 75 pathogenic changes around while only 4 benign (95%) in NM_015915.5
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 14-50591011-G-A is Pathogenic according to our data. Variant chr14-50591011-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157549.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr14-50591011-G-A is described in Lovd as [Pathogenic]. Variant chr14-50591011-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATL1	NM_015915.5	c.353G>A	p.Arg118Gln	missense_variant	3/14	ENST00000358385.12
ATL1	NM_001127713.1	c.353G>A	p.Arg118Gln	missense_variant	4/14
ATL1	NM_181598.4	c.353G>A	p.Arg118Gln	missense_variant	3/13
ATL1	XM_047431430.1	c.353G>A	p.Arg118Gln	missense_variant	4/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATL1	ENST00000358385.12	c.353G>A	p.Arg118Gln	missense_variant	3/14	1	NM_015915.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461260 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726946

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 3A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 22, 2023

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 118 of the ATL1 protein (p.Arg118Gln). This missense change has been observed in individual(s) with autosomal recessive hereditary spastic paraplegia (PMID: 24473461). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 157549). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Spastic Paraplegia, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The ATL1 c.353G>A (p.Arg118Gln) missense variant has been reported in one study in a large consanguineous family in which it was found in a homozygous state in all six family members affected with early onset spastic paraplegia (Khan et al. 2014). The p.Arg118Gln variant was also found in a heterozygous state in seven asymptomatic family members who did not show clinical symptoms of spastic paraplegia. While the variant in this family segregates with disease following an autosomal recessive pattern of inheritance, this disorder largely follows a dominant mode of inheritance. Control data are not available for the p.Arg118Gln variant which is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium or the Genome Aggregation Database, in a region of good coverage, suggesting that this is a rare variant. Based on the evidence, the p.Arg118Gln variant is classified as a variant of unknown significance but suspicious for pathogenicity for a recessive form of spastic paraplegia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Oct 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	.;D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	3.4	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.57
MutPred		0.54		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP		0.92
MPC		1.8
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.84
gMVP		0.84

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: rs606231265; hg19: chr14-51057729;