chr14-50587880-A-G

Position:

• chr14-50587880-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015915.5(ATL1):​c.84A>G​(p.Pro28=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,613,942 control chromosomes in the GnomAD database, including 17,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3045 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14390 hom.)
• Consequence: ATL1 NM_015915.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -2.70

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 14-50587880-A-G is Benign according to our data. Variant chr14-50587880-A-G is described in ClinVar as [Benign]. Clinvar id is 21534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50587880-A-G is described in Lovd as [Pathogenic]. Variant chr14-50587880-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.7 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATL1	NM_015915.5	c.84A>G	p.Pro28=	synonymous_variant	2/14	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1	c.84A>G	p.Pro28=	synonymous_variant	3/14		NP_001121185.1
ATL1	NM_181598.4	c.84A>G	p.Pro28=	synonymous_variant	2/13		NP_853629.2
ATL1	XM_047431430.1	c.84A>G	p.Pro28=	synonymous_variant	3/15		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12	c.84A>G	p.Pro28=	synonymous_variant	2/14	1	NM_015915.5	ENSP00000351155	P3

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27557 AN: 151988 Hom.: 3043 Cov.: 32

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.0768

Gnomad SAS AF: 0.0771

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.173

GnomAD3 exomes AF: 0.131 AC: 32973 AN: 251472 Hom.: 2699 AF XY: 0.126 AC XY: 17148 AN XY: 135908

Gnomad AFR exome AF: 0.319

Gnomad AMR exome AF: 0.0894

Gnomad ASJ exome AF: 0.184

Gnomad EAS exome AF: 0.0746

Gnomad SAS exome AF: 0.0758

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.135 AC: 197220 AN: 1461836 Hom.: 14390 Cov.: 33 AF XY: 0.132 AC XY: 96205 AN XY: 727224

Gnomad4 AFR exome AF: 0.326

Gnomad4 AMR exome AF: 0.0931

Gnomad4 ASJ exome AF: 0.184

Gnomad4 EAS exome AF: 0.0740

Gnomad4 SAS exome AF: 0.0765

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.181 AC: 27582 AN: 152106 Hom.: 3045 Cov.: 32 AF XY: 0.179 AC XY: 13287 AN XY: 74360

Gnomad4 AFR AF: 0.316

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.189

Gnomad4 EAS AF: 0.0770

Gnomad4 SAS AF: 0.0779

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.170

Alfa AF: 0.157 Hom.: 1125

Bravo AF: 0.187

Asia WGS AF: 0.0990 AC: 346 AN: 3478

EpiCase AF: 0.137

EpiControl AF: 0.137

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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. -

Hereditary spastic paraplegia 3A Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Neuropathy, hereditary sensory, type 1D Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

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

Apr 30, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.8
DANN	Benign	0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs35014209; hg19: chr14-51054598; COSMIC: COSV63295932; COSMIC: COSV63295932;