rs377736535

Positions:

• chr14-50590969-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_015915.5(ATL1):​c.311A>G​(p.Asn104Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. N104I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 7.50

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 Uncertain_significance. Variant got 3 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 where missense usually causes diseases, ATL1
• BP4: Computational evidence support a benign effect (MetaRNN=0.17723271).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATL1	NM_015915.5	c.311A>G	p.Asn104Ser	missense_variant	3/14	ENST00000358385.12
ATL1	NM_001127713.1	c.311A>G	p.Asn104Ser	missense_variant	4/14
ATL1	NM_181598.4	c.311A>G	p.Asn104Ser	missense_variant	3/13
ATL1	XM_047431430.1	c.311A>G	p.Asn104Ser	missense_variant	4/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATL1	ENST00000358385.12	c.311A>G	p.Asn104Ser	missense_variant	3/14	1	NM_015915.5	P3

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 251278 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1461626 Hom.: 0 Cov.: 30 AF XY: 0.0000413 AC XY: 30 AN XY: 727110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74366

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000676 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 13, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	ATL1: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2018	A variant of uncertain significance has been identified in the ATL1 gene. The N104S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N104S variant is observed in 7/66676 (0.01%) alleles from individuals of Europea background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N104S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Hereditary spastic paraplegia 3A Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Nov 18, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 104 of the ATL1 protein (p.Asn104Ser). This variant is present in population databases (rs377736535, gnomAD 0.02%). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 28736820). ClinVar contains an entry for this variant (Variation ID: 450586). 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 with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Benign	0.95
Eigen	Benign	-0.00087
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.89	L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.096
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.0020	.;B;.
Vest4		0.11
MVP		0.71
MPC		0.52
ClinPred		0.17	T
GERP RS		5.6
Varity_R		0.25
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs377736535; hg19: chr14-51057687;