rs1555364149

Variant names:

• chr14-50593859-C-A
• rs1555364149
• NM_015915.5:c.536C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_015915.5(ATL1):​c.536C>A​(p.Ser179Tyr) 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.83

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 domain GB1/RHD3-type G (size 245) in uniprot entity ATLA1_HUMAN there are 38 pathogenic changes around while only 0 benign (100%) in NM_015915.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ATL1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 60 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 2.6313 (below the threshold of 3.09). Trascript score misZ: 3.8383 (above the threshold of 3.09). GenCC associations: The gene is linked to hereditary sensory and autonomic neuropathy type 1, hereditary spastic paraplegia 3A, neuropathy, hereditary sensory, type 1D.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 14-50593859-C-A is Pathogenic according to our data. Variant chr14-50593859-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 538581.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATL1	NM_015915.5	c.536C>A	p.Ser179Tyr	missense_variant	Exon 5 of 14	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1	c.536C>A	p.Ser179Tyr	missense_variant	Exon 6 of 14		NP_001121185.1
ATL1	NM_181598.4	c.536C>A	p.Ser179Tyr	missense_variant	Exon 5 of 13		NP_853629.2
ATL1	XM_047431430.1	c.536C>A	p.Ser179Tyr	missense_variant	Exon 6 of 15		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12	c.536C>A	p.Ser179Tyr	missense_variant	Exon 5 of 14	1	NM_015915.5	ENSP00000351155.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1452090 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 723042

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 3A Pathogenic:1

Aug 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATL1 protein function. ClinVar contains an entry for this variant (Variation ID: 538581). This missense change has been observed in individual(s) with ATL1-related conditions (Invitae). In at least one individual the variant was observed to be de novo. 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 179 of the ATL1 protein (p.Ser179Tyr). -

not provided Uncertain:1

Jun 01, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	.;D;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	-0.042	T
MutationAssessor	Pathogenic	3.3	M;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.028	D;D;T
Polyphen		1.0	.;D;.
Vest4		0.80
MutPred		0.65		Loss of disorder (P = 0.0642);Loss of disorder (P = 0.0642);.;
MVP		0.79
MPC		1.9
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.90
gMVP		0.90

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: rs1555364149; hg19: chr14-51060577;