chr14-50595639-G-A

Variant names:

• chr14-50595639-G-A
• rs3759588
• NM_015915.5:c.630+7G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Publications: 7 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: Benign. The variant received -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 VariationId is 136428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATL1	NM_015915.5	c.630+7G>A		splice_region_variant, intron_variant	Intron 6 of 13	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1	c.630+7G>A		splice_region_variant, intron_variant	Intron 7 of 13		NP_001121185.1
ATL1	NM_181598.4	c.630+7G>A		splice_region_variant, intron_variant	Intron 6 of 12		NP_853629.2
ATL1	XM_047431430.1	c.630+7G>A		splice_region_variant, intron_variant	Intron 7 of 14		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12	c.630+7G>A		splice_region_variant, intron_variant	Intron 6 of 13	1	NM_015915.5	ENSP00000351155.7

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25933 AN: 151834 Hom.: 2588 Cov.: 31

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

GnomAD2 exomes AF: 0.129 AC: 32517 AN: 251246 AF XY: 0.125

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 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.: 32 AF XY: 0.132 AC XY: 96141 AN XY: 726470

African (AFR) AF: 0.281 AC: 9405 AN: 33414

American (AMR) AF: 0.0919 AC: 4108 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 5468 AN: 26118

East Asian (EAS) AF: 0.0733 AC: 2909 AN: 39660

South Asian (SAS) AF: 0.0764 AC: 6585 AN: 86222

European-Finnish (FIN) AF: 0.131 AC: 6970 AN: 53354

Middle Eastern (MID) AF: 0.183 AC: 1053 AN: 5760

European-Non Finnish (NFE) AF: 0.137 AC: 151633 AN: 1110476

Other (OTH) AF: 0.141 AC: 8524 AN: 60338

GnomAD4 genome AF: 0.171 AC: 25951 AN: 151952 Hom.: 2587 Cov.: 31 AF XY: 0.168 AC XY: 12491 AN XY: 74272

African (AFR) AF: 0.276 AC: 11443 AN: 41402

American (AMR) AF: 0.124 AC: 1896 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 736 AN: 3462

East Asian (EAS) AF: 0.0767 AC: 397 AN: 5178

South Asian (SAS) AF: 0.0781 AC: 376 AN: 4812

European-Finnish (FIN) AF: 0.136 AC: 1436 AN: 10552

Middle Eastern (MID) AF: 0.226 AC: 66 AN: 292

European-Non Finnish (NFE) AF: 0.134 AC: 9129 AN: 67972

Other (OTH) AF: 0.162 AC: 342 AN: 2110

Alfa AF: 0.155 Hom.: 1224

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

Submissions by phenotype

not specified Benign:4

Dec 30, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 24, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 3A Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATL1-related disorder Benign:1

Jul 05, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.8
DANN	Benign	0.51
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3759588; hg19: chr14-51062357; COSMIC: COSV63295924; COSMIC: COSV63295924;