14-50621893-G-T

Variant names:

• chr14-50621893-G-T
• rs1555365512
• NM_015915.5:c.1041G>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP2 PP3 PP5_Moderate

The NM_015915.5(ATL1):​c.1041G>T​(p.Met347Ile) 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 Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M347T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

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]

ATL1 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 3A

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• neuropathy, hereditary sensory, type 1D

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• hereditary sensory and autonomic neuropathy type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS1: Transcript NM_015915.5 (ATL1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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 chr14-50621892-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 805504.
• 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 spastic paraplegia 3A, neuropathy, hereditary sensory, type 1D, hereditary sensory and autonomic neuropathy type 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777
• PP5: Variant 14-50621893-G-T is Pathogenic according to our data. Variant chr14-50621893-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2444332.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015915.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL1	NM_015915.5	MANE Select	c.1041G>T	p.Met347Ile	missense	Exon 10 of 14	NP_056999.2
	ATL1	NM_001127713.1		c.1041G>T	p.Met347Ile	missense	Exon 11 of 14	NP_001121185.1
	ATL1	NM_181598.4		c.1041G>T	p.Met347Ile	missense	Exon 10 of 13	NP_853629.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL1	ENST00000358385.12	TSL:1 MANE Select	c.1041G>T	p.Met347Ile	missense	Exon 10 of 14	ENSP00000351155.7
	ATL1	ENST00000441560.6	TSL:1	c.1041G>T	p.Met347Ile	missense	Exon 11 of 14	ENSP00000413675.2
	ATL1	ENST00000682037.1		c.1041G>T	p.Met347Ile	missense	Exon 10 of 14	ENSP00000508289.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 3A Pathogenic:1

Feb 23, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.74; 3Cnet: 0.86). Different nucleotide change resulting in same amino acid change has been previously reported to be associated with ATL1 related disorder (PMID: 31594988). Different missense changes at the same codon (p.Met347Leu, p.Met347Thr) have been reported to be associated with ATL1 related disorder (PMID: 21321493, 28736820). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	2.0	M
PhyloP100		10
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.74
Sift	Benign	0.17	T
Sift4G	Benign	0.12	T
Polyphen		0.26	B
Vest4		0.66
MutPred		0.63		Loss of helix (P = 0.0237)
MVP		0.97
MPC		0.74
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.84
gMVP		0.75
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555365512; hg19: chr14-51088611;