rs3759588

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015915.5(ATL1):c.630+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,612,016 control chromosomes in the GnomAD database, including 16,779 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2587 hom., cov: 31)

Exomes 𝑓: 0.13 ( 14192 hom. )

Consequence

ATL1
NM_015915.5 splice_region, intron

Scores

Splicing: ADA: 0.00008445

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.130

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 14-50595639-G-A is Benign according to our data. Variant chr14-50595639-G-A is described in ClinVar as [Benign]. Clinvar id is 136428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50595639-G-A is described in Lovd as [Pathogenic]. Variant chr14-50595639-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
ATL1	NM_015915.5 linkuse as main transcript	c.630+7G>A	splice_region_variant, intron_variant	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1 linkuse as main transcript	c.630+7G>A	splice_region_variant, intron_variant		NP_001121185.1
ATL1	NM_181598.4 linkuse as main transcript	c.630+7G>A	splice_region_variant, intron_variant		NP_853629.2
ATL1	XM_047431430.1 linkuse as main transcript	c.630+7G>A	splice_region_variant, intron_variant		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12 linkuse as main transcript	c.630+7G>A		splice_region_variant, intron_variant		1	NM_015915.5	ENSP00000351155	P3	Q8WXF7-1

Frequencies

GnomAD3 genomes

AF:

0.171

AC:

25933

AN:

151834

Hom.:

2588

Cov.:

show subpopulations

Gnomad AFR

AF:

0.277

Gnomad AMI

AF:

0.143

Gnomad AMR

AF:

0.124

Gnomad ASJ

AF:

0.213

Gnomad EAS

AF:

0.0765

Gnomad SAS

AF:

0.0775

Gnomad FIN

AF:

0.136

Gnomad MID

AF:

0.229

Gnomad NFE

AF:

0.134

Gnomad OTH

AF:

0.165

GnomAD3 exomes

AF:

0.129

AC:

32517

AN:

251246

Hom.:

2523

AF XY:

0.125

AC XY:

16999

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.275

Gnomad AMR exome

AF:

0.0885

Gnomad ASJ exome

AF:

0.209

Gnomad EAS exome

AF:

0.0735

Gnomad SAS exome

AF:

0.0757

Gnomad FIN exome

AF:

0.136

Gnomad NFE exome

AF:

0.135

Gnomad OTH exome

AF:

0.149

GnomAD4 exome

AF:

0.135

AC:

196655

AN:

1460064

Hom.:

14192

Cov.:

AF XY:

0.132

AC XY:

96141

AN XY:

726470

show subpopulations

Gnomad4 AFR exome

AF:

0.281

Gnomad4 AMR exome

AF:

0.0919

Gnomad4 ASJ exome

AF:

0.209

Gnomad4 EAS exome

AF:

0.0733

Gnomad4 SAS exome

AF:

0.0764

Gnomad4 FIN exome

AF:

0.131

Gnomad4 NFE exome

AF:

0.137

Gnomad4 OTH exome

AF:

0.141

GnomAD4 genome

AF:

0.171

AC:

25951

AN:

151952

Hom.:

2587

Cov.:

AF XY:

0.168

AC XY:

12491

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.276

Gnomad4 AMR

AF:

0.124

Gnomad4 ASJ

AF:

0.213

Gnomad4 EAS

AF:

0.0767

Gnomad4 SAS

AF:

0.0781

Gnomad4 FIN

AF:

0.136

Gnomad4 NFE

AF:

0.134

Gnomad4 OTH

AF:

0.162

Alfa

AF:

0.156

Hom.:

923

Bravo

AF:

0.174

Asia WGS

AF:

0.0960

AC:

335

AN:

3478

EpiCase

AF:

0.138

EpiControl

AF:

0.138

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hereditary spastic paraplegia 3A

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

ATL1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 05, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Neuropathy, hereditary sensory, type 1D

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Hereditary spastic paraplegia 3A;C3150972:Neuropathy, hereditary sensory, type 1D

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 24, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

2.8

DANN

Benign

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000084

dbscSNV1_RF

Benign

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over