rs119476047

Positions:

• chr14-50614425-C-A
• chr14-50614425-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The ENST00000358385.12(ATL1):​c.776C>A​(p.Ser259Tyr) 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. S259F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATL1 ENST00000358385.12 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.85

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 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000358385.12
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-50614425-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 949900.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}.
• 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, 0.968
• PP5: Variant 14-50614425-C-A is Pathogenic according to our data. Variant chr14-50614425-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 4347.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-50614425-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATL1	NM_015915.5	c.776C>A	p.Ser259Tyr	missense_variant	8/14	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1	c.776C>A	p.Ser259Tyr	missense_variant	9/14		NP_001121185.1
ATL1	NM_181598.4	c.776C>A	p.Ser259Tyr	missense_variant	8/13		NP_853629.2
ATL1	XM_047431430.1	c.776C>A	p.Ser259Tyr	missense_variant	9/15		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12	c.776C>A	p.Ser259Tyr	missense_variant	8/14	1	NM_015915.5	ENSP00000351155	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 3A Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 05, 2022	ClinVar contains an entry for this variant (Variation ID: 4347). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser259 amino acid residue in ATL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19459885, 29691679). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ATL1 function (PMID: 25761634). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individuals with autosomal dominant hereditary spastic paraplegia (PMID: 11685207, 29907907). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 259 of the ATL1 protein (p.Ser259Tyr). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2001	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	.;D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.026	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.97	.;D
Vest4		0.83
MutPred		0.91		Gain of methylation at K255 (P = 0.0869);Gain of methylation at K255 (P = 0.0869);
MVP		0.91
MPC		1.5
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.86
gMVP		0.76

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: rs119476047; hg19: chr14-51081143;