rs146975855

Variant names:

• chr14-50613297-C-T
• rs146975855
• NM_015915.5:c.669C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015915.5(ATL1):​c.669C>T​(p.Tyr223Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000632 in 1,613,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (0 hom.)
• Consequence: ATL1 NM_015915.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.32
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 14-50613297-C-T is Benign according to our data. Variant chr14-50613297-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 313298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.33 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000591 (90/152158) while in subpopulation NFE AF = 0.000882 (60/68012). AF 95% confidence interval is 0.000703. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 90 AD,SD gene.

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.669C>T	p.Tyr223Tyr	synonymous	Exon 7 of 14	NP_056999.2
	ATL1	NM_001127713.1		c.669C>T	p.Tyr223Tyr	synonymous	Exon 8 of 14	NP_001121185.1	Q53F53
	ATL1	NM_181598.4		c.669C>T	p.Tyr223Tyr	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.669C>T	p.Tyr223Tyr	synonymous	Exon 7 of 14	ENSP00000351155.7	Q8WXF7-1
	ATL1	ENST00000441560.6	TSL:1	c.669C>T	p.Tyr223Tyr	synonymous	Exon 8 of 14	ENSP00000413675.2	Q8WXF7-2
	ATL1	ENST00000682037.1		c.669C>T	p.Tyr223Tyr	synonymous	Exon 7 of 14	ENSP00000508289.1	A0A804HLC1

Frequencies

GnomAD3 genomes AF: 0.000599 AC: 91 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000812 AC: 204 AN: 251238 AF XY: 0.000928

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000933

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000637 AC: 930 AN: 1461056 Hom.: 0 Cov.: 31 AF XY: 0.000669 AC XY: 486 AN XY: 726860

African (AFR) AF: 0.000150 AC: 5 AN: 33444

American (AMR) AF: 0.000336 AC: 15 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00425 AC: 111 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000881 AC: 76 AN: 86232

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53408

Middle Eastern (MID) AF: 0.00434 AC: 24 AN: 5534

European-Non Finnish (NFE) AF: 0.000571 AC: 635 AN: 1111624

Other (OTH) AF: 0.00104 AC: 63 AN: 60338

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.000511 AC XY: 38 AN XY: 74378

African (AFR) AF: 0.000193 AC: 8 AN: 41504

American (AMR) AF: 0.000197 AC: 3 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000597

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Hereditary spastic paraplegia 3A (3)
-	-	1	ATL1-related disorder (1)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuropathy, hereditary sensory, type 1D (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.7
DANN	Benign	0.33
PhyloP100		-1.3
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146975855; hg19: chr14-51080015; COSMIC: COSV100613402; COSMIC: COSV100613402;