rs1060502971

Positions:

• chr14-50591578-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP5

The NM_015915.5(ATL1):​c.461A>G​(p.Gln154Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Q154E) has been classified as Likely pathogenic.

• 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: 9.23

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 8 ACMG points.

• PM1: In a strand (size 3) in uniprot entity ATLA1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_015915.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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 14-50591578-A-G is Pathogenic according to our data. Variant chr14-50591578-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 410596.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATL1	NM_015915.5	c.461A>G	p.Gln154Arg	missense_variant	4/14	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1	c.461A>G	p.Gln154Arg	missense_variant	5/14		NP_001121185.1
ATL1	NM_181598.4	c.461A>G	p.Gln154Arg	missense_variant	4/13		NP_853629.2
ATL1	XM_047431430.1	c.461A>G	p.Gln154Arg	missense_variant	5/15		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12	c.461A>G	p.Gln154Arg	missense_variant	4/14	1	NM_015915.5	ENSP00000351155	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

Abnormal pyramidal sign Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

-

- -

Hereditary spastic paraplegia 3A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 03, 2020

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. However, a different missense substitution at this codon (p.Gln154Glu) is reported to be deleterious (PMID: 20932283). This indicates that the p.Gln154 residue is important for ATL1 protein function. 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ATL1-related disease. This sequence change replaces glutamine with arginine at codon 154 of the ATL1 protein (p.Gln154Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	.;D;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.1	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0060	D;D;T
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.16	.;B;.
Vest4		0.76
MutPred		0.39		Gain of phosphorylation at T156 (P = 0.0839);Gain of phosphorylation at T156 (P = 0.0839);.;
MVP		0.90
MPC		0.80
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.82
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: rs1060502971; hg19: chr14-51058296;