chr14-50614425-C-T

Variant names:

• chr14-50614425-C-T
• rs119476047
• NM_015915.5:c.776C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_015915.5(ATL1):​c.776C>T​(p.Ser259Phe) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S259Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.85

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a helix (size 12) in uniprot entity ATLA1_HUMAN there are 8 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 chr14-50614425-C-A is described in Lovd as [Pathogenic].
• 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, 0.969
• PP5: Variant 14-50614425-C-T is Pathogenic according to our data. Variant chr14-50614425-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 949900.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}. Variant chr14-50614425-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATL1	NM_015915.5	c.776C>T	p.Ser259Phe	missense_variant	Exon 8 of 14	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1	c.776C>T	p.Ser259Phe	missense_variant	Exon 9 of 14		NP_001121185.1
ATL1	NM_181598.4	c.776C>T	p.Ser259Phe	missense_variant	Exon 8 of 13		NP_853629.2
ATL1	XM_047431430.1	c.776C>T	p.Ser259Phe	missense_variant	Exon 9 of 15		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12	c.776C>T	p.Ser259Phe	missense_variant	Exon 8 of 14	1	NM_015915.5	ENSP00000351155.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Jan 03, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 3A Pathogenic:1

Feb 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser259 amino acid residue in ATL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11685207, 29907907). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 949900). This missense change has been observed in individuals with clinical features of autosomal dominant hereditary spastic paraplegia (PMID: 19459885, 29691679). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 259 of the ATL1 protein (p.Ser259Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.82
MutPred		0.91		Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);
MVP		0.93
MPC		1.8
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.89
gMVP		0.75

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: rs119476047; hg19: chr14-51081143;