rs35014209

Variant names:

• chr14-50587880-A-G
• rs35014209
• NM_015915.5:c.84A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015915.5(ATL1):​c.84A>G​(p.Pro28Pro) 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
• Publications: 13 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 -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 VariationId is 21534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015915.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL1	NM_015915.5	MANE Select	c.84A>G	p.Pro28Pro	synonymous	Exon 2 of 14	NP_056999.2
	ATL1	NM_001127713.1		c.84A>G	p.Pro28Pro	synonymous	Exon 3 of 14	NP_001121185.1
	ATL1	NM_181598.4		c.84A>G	p.Pro28Pro	synonymous	Exon 2 of 13	NP_853629.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL1	ENST00000358385.12	TSL:1 MANE Select	c.84A>G	p.Pro28Pro	synonymous	Exon 2 of 14	ENSP00000351155.7
	ATL1	ENST00000441560.6	TSL:1	c.84A>G	p.Pro28Pro	synonymous	Exon 3 of 14	ENSP00000413675.2
	ATL1	ENST00000682037.1		c.84A>G	p.Pro28Pro	synonymous	Exon 2 of 14	ENSP00000508289.1

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

GnomAD2 exomes AF: 0.131 AC: 32973 AN: 251472 AF XY: 0.126

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 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

African (AFR) AF: 0.326 AC: 10904 AN: 33480

American (AMR) AF: 0.0931 AC: 4166 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 4817 AN: 26132

East Asian (EAS) AF: 0.0740 AC: 2936 AN: 39698

South Asian (SAS) AF: 0.0765 AC: 6603 AN: 86258

European-Finnish (FIN) AF: 0.131 AC: 7012 AN: 53416

Middle Eastern (MID) AF: 0.188 AC: 1082 AN: 5768

European-Non Finnish (NFE) AF: 0.136 AC: 151137 AN: 1111964

Other (OTH) AF: 0.142 AC: 8563 AN: 60396

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

African (AFR) AF: 0.316 AC: 13116 AN: 41466

American (AMR) AF: 0.128 AC: 1961 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 654 AN: 3468

East Asian (EAS) AF: 0.0770 AC: 398 AN: 5168

South Asian (SAS) AF: 0.0779 AC: 376 AN: 4824

European-Finnish (FIN) AF: 0.136 AC: 1434 AN: 10576

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9085 AN: 67992

Other (OTH) AF: 0.170 AC: 360 AN: 2114

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Hereditary spastic paraplegia 3A (4)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Neuropathy, hereditary sensory, type 1D (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.8
DANN	Benign	0.70
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

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