rs35044504

Variant names:

• chr14-50613333-C-T
• rs35044504
• NM_015915.5:c.705C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_015915.5(ATL1):​c.705C>T​(p.Phe235Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00419 in 1,612,768 control chromosomes in the GnomAD database, including 226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (108 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (118 hom.)
• Consequence: ATL1 NM_015915.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.980
• 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• neuropathy, hereditary sensory, type 1D

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• hereditary sensory and autonomic neuropathy type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 14-50613333-C-T is Benign according to our data. Variant chr14-50613333-C-T is described in ClinVar as Benign. ClinVar VariationId is 313300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.98 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0754 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.705C>T	p.Phe235Phe	synonymous	Exon 7 of 14	NP_056999.2
	ATL1	NM_001127713.1		c.705C>T	p.Phe235Phe	synonymous	Exon 8 of 14	NP_001121185.1	Q53F53
	ATL1	NM_181598.4		c.705C>T	p.Phe235Phe	synonymous	Exon 7 of 13	NP_853629.2	Q8WXF7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATL1	ENST00000358385.12	TSL:1 MANE Select	c.705C>T	p.Phe235Phe	synonymous	Exon 7 of 14	ENSP00000351155.7	Q8WXF7-1
	ATL1	ENST00000441560.6	TSL:1	c.705C>T	p.Phe235Phe	synonymous	Exon 8 of 14	ENSP00000413675.2	Q8WXF7-2
	ATL1	ENST00000682037.1		c.705C>T	p.Phe235Phe	synonymous	Exon 7 of 14	ENSP00000508289.1	A0A804HLC1

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3437 AN: 151916 Hom.: 110 Cov.: 32

Gnomad AFR AF: 0.0778

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0216

GnomAD2 exomes AF: 0.00609 AC: 1528 AN: 251102 AF XY: 0.00447

Gnomad AFR exome AF: 0.0810

Gnomad AMR exome AF: 0.00461

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00227 AC: 3312 AN: 1460734 Hom.: 118 Cov.: 31 AF XY: 0.00187 AC XY: 1362 AN XY: 726734

African (AFR) AF: 0.0786 AC: 2625 AN: 33392

American (AMR) AF: 0.00517 AC: 231 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00326 AC: 18 AN: 5518

European-Non Finnish (NFE) AF: 0.000121 AC: 135 AN: 1111420

Other (OTH) AF: 0.00494 AC: 298 AN: 60326

GnomAD4 genome AF: 0.0226 AC: 3440 AN: 152034 Hom.: 108 Cov.: 32 AF XY: 0.0224 AC XY: 1661 AN XY: 74304

African (AFR) AF: 0.0777 AC: 3218 AN: 41438

American (AMR) AF: 0.0106 AC: 162 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68006

Other (OTH) AF: 0.0214 AC: 45 AN: 2102

Alfa AF: 0.0103 Hom.: 46

Bravo AF: 0.0263

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Hereditary spastic paraplegia 3A (3)
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Neuropathy, hereditary sensory, type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	9.5
DANN	Benign	0.68
PhyloP100		0.98
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs35044504; hg19: chr14-51080051;