rs149340140

Variant names:

• chr14-50628084-C-A
• rs149340140
• NM_015915.5:c.1173C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-50628084-C-A
• chr14-50628084-C-G
• chr14-50628084-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_015915.5(ATL1):​c.1173C>A​(p.His391Gln) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. H391H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0510
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain 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 spastic paraplegia 3A, neuropathy, hereditary sensory, type 1D, hereditary sensory and autonomic neuropathy type 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATL1	NM_015915.5	c.1173C>A	p.His391Gln	missense_variant	Exon 12 of 14	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1	c.1173C>A	p.His391Gln	missense_variant	Exon 13 of 14		NP_001121185.1
ATL1	NM_181598.4	c.1173C>A	p.His391Gln	missense_variant	Exon 12 of 13		NP_853629.2
ATL1	XM_047431430.1	c.1173C>A	p.His391Gln	missense_variant	Exon 13 of 15		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12	c.1173C>A	p.His391Gln	missense_variant	Exon 12 of 14	1	NM_015915.5	ENSP00000351155.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 3A Uncertain:1

Mar 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 391 of the ATL1 protein (p.His391Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATL1-related conditions. 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 expected to disrupt ATL1 protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	.;D
Eigen	Benign	-0.033
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.8	M;M
PhyloP100		0.051
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.2	D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.96
MutPred		0.57		Gain of disorder (P = 0.0588);Gain of disorder (P = 0.0588);
MVP		0.95
MPC		1.7
ClinPred		0.99	D
GERP RS		-1.3
Varity_R		0.97
gMVP		0.87
Mutation Taster		=18/82	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: rs149340140; hg19: chr14-51094802;