rs886041897

chr14-50591595-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_015915.5(ATL1):c.478T>C(p.Ser160Pro) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.94

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 7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_015915.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ATL1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783
• PP5: Variant 14-50591595-T-C is Pathogenic according to our data. Variant chr14-50591595-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 280749.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATL1	NM_015915.5	c.478T>C	p.Ser160Pro	missense_variant	4/14	ENST00000358385.12
ATL1	NM_001127713.1	c.478T>C	p.Ser160Pro	missense_variant	5/14
ATL1	NM_181598.4	c.478T>C	p.Ser160Pro	missense_variant	4/13
ATL1	XM_047431430.1	c.478T>C	p.Ser160Pro	missense_variant	5/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATL1	ENST00000358385.12	c.478T>C	p.Ser160Pro	missense_variant	4/14	1	NM_015915.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 04, 2016

The S160P variant in the ATL1 gene has not been reported previously as a pathogenic variant, nor asa benign variant, to our knowledge. The S160P variant was not observed in approximately 6500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. The S160P variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure asthese residues differ in polarity, charge, size and/or other properties. This substitution occurs at aposition that is conserved across species. In silico analysis is inconsistent in its predictions as towhether or not the variant is damaging to the protein structure/function. However, missense variantsin nearby residues (T156I, L157W, A161P, T162P, V163A) have been reported in the Human GeneMutation Database in association with spastic paraplegia (Stenson et al., 2014), supporting thefunctional importance of this region of the protein. We interpret S160P as a pathogenic variant. -

Hereditary spastic paraplegia 3A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2018

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with ATL1-related disease. ClinVar contains an entry for this variant (Variation ID: 280749). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with proline at codon 160 of the ATL1 protein (p.Ser160Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.1	N;N;N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.98	.;D;.
Vest4		0.82
MutPred		0.60		Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);.;
MVP		0.95
MPC		1.7
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.89
gMVP		0.98

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: rs886041897; hg19: chr14-51058313;