14-50587925-C-G

Variant names:

• chr14-50587925-C-G
• rs17850684
• NM_015915.5:c.129C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_015915.5(ATL1):​c.129C>G​(p.Asp43Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D43N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.39
• Publications: 4 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: Uncertain_significance. The variant received 1 ACMG points.

• 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 spastic paraplegia 3A, neuropathy, hereditary sensory, type 1D, hereditary sensory and autonomic neuropathy type 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20358112).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATL1	NM_015915.5	c.129C>G	p.Asp43Glu	missense_variant	Exon 2 of 14	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1	c.129C>G	p.Asp43Glu	missense_variant	Exon 3 of 14		NP_001121185.1
ATL1	NM_181598.4	c.129C>G	p.Asp43Glu	missense_variant	Exon 2 of 13		NP_853629.2
ATL1	XM_047431430.1	c.129C>G	p.Asp43Glu	missense_variant	Exon 3 of 15		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12	c.129C>G	p.Asp43Glu	missense_variant	Exon 2 of 14	1	NM_015915.5	ENSP00000351155.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Hereditary spastic paraplegia 3A Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	.;T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.97	L;.;L
PhyloP100		1.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.0030	.;.;B
Vest4		0.38
MutPred		0.22		Loss of sheet (P = 0.0054);Loss of sheet (P = 0.0054);Loss of sheet (P = 0.0054);
MVP		0.72
MPC		0.62
ClinPred		0.31	T
GERP RS		0.48
Varity_R		0.50
gMVP		0.33
Mutation Taster		=29/71	disease causing

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

Other links and lift over

dbSNP: rs17850684; hg19: chr14-51054643;