14-50560298-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_015915.5(ATL1):c.33G>C(p.Trp11Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000109 in 1,461,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ATL1 NM_015915.5 missense, splice_region
• Scores: Splicing: ADA: 0.01124
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.93

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]

MAP4K5 (HGNC:6867): (mitogen-activated protein kinase kinase kinase kinase 5) This gene encodes a member of the serine/threonine protein kinase family, that is highly similar to yeast SPS1/STE20 kinase. Yeast SPS1/STE20 functions near the beginning of the MAP kinase signal cascades that is essential for yeast pheromone response. This kinase was shown to activate Jun kinase in mammalian cells, which suggested a role in stress response. Two alternatively spliced transcript variants encoding the same protein have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• 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=0.23456874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATL1	NM_015915.5	c.33G>C	p.Trp11Cys	missense_variant, splice_region_variant	1/14	ENST00000358385.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATL1	ENST00000358385.12	c.33G>C	p.Trp11Cys	missense_variant, splice_region_variant	1/14	1	NM_015915.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 249100 Hom.: 0 AF XY: 0.0000297 AC XY: 4 AN XY: 134830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461568 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 727110

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: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 3A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2022

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1416672). This variant has not been reported in the literature in individuals affected with ATL1-related conditions. This variant is present in population databases (rs765421231, gnomAD 0.005%). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 11 of the ATL1 protein (p.Trp11Cys). -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2021

The p.W11C variant (also known as c.33G>C), located in coding exon 1 of the ATL1 gene, results from a G to C substitution at nucleotide position 33. The tryptophan at codon 11 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.23
Cadd	Pathogenic	30
Dann	Uncertain	0.98
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.34	N;.;.;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.11	N;N;D;N
REVEL	Uncertain	0.30
Sift	Benign	0.083	T;T;.;T
Sift4G	Benign	0.070	T;D;D;T
Polyphen		0.99	.;.;.;D
Vest4		0.53
MutPred		0.31		Loss of MoRF binding (P = 0.0295);Loss of MoRF binding (P = 0.0295);Loss of MoRF binding (P = 0.0295);Loss of MoRF binding (P = 0.0295);
MVP		0.55
MPC		1.3
ClinPred		0.28	T
GERP RS		3.5
Varity_R		0.19
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.011
dbscSNV1_RF	Benign	0.12
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: rs765421231; hg19: chr14-51027016;