Genetic Variant ATL1:c.35-74G>C (chr14-50587757-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015915.5(ATL1):c.35-74G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0433 in 1,591,626 control chromosomes in the GnomAD database, including 1,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 104 hom., cov: 32)

Exomes 𝑓: 0.044 ( 1653 hom. )

Consequence

ATL1
NM_015915.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.387

Publications

1 publications found

Variant links:

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

ATL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 14-50587757-G-C is Benign according to our data. Variant chr14-50587757-G-C is described in ClinVar as Benign. ClinVar VariationId is 1262532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0549 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATL1	NM_015915.5	MANE Select	c.35-74G>C	intron	N/A	NP_056999.2
ATL1	NM_001127713.1		c.35-74G>C	intron	N/A	NP_001121185.1	Q53F53
ATL1	NM_181598.4		c.35-74G>C	intron	N/A	NP_853629.2	Q8WXF7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATL1	ENST00000358385.12	TSL:1 MANE Select	c.35-74G>C	intron	N/A	ENSP00000351155.7	Q8WXF7-1
ATL1	ENST00000441560.6	TSL:1	c.35-74G>C	intron	N/A	ENSP00000413675.2	Q8WXF7-2
ATL1	ENST00000682037.1		c.35-74G>C	intron	N/A	ENSP00000508289.1	A0A804HLC1

Frequencies

GnomAD3 genomes

AF:

0.0375

AC:

5711

AN:

152132

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0245

Gnomad AMI

AF:

0.0868

Gnomad AMR

AF:

0.0396

Gnomad ASJ

AF:

0.0386

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0120

Gnomad FIN

AF:

0.0368

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0488

Gnomad OTH

AF:

0.0459

GnomAD4 exome

AF:

0.0439

AC:

63209

AN:

1439376

Hom.:

1653

AF XY:

0.0435

AC XY:

31249

AN XY:

717642

show subpopulations

African (AFR)

AF:

0.0224

AC:

738

AN:

32986

American (AMR)

AF:

0.0281

AC:

1253

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.0384

AC:

1000

AN:

26022

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39582

South Asian (SAS)

AF:

0.0117

AC:

1002

AN:

85540

European-Finnish (FIN)

AF:

0.0357

AC:

1830

AN:

51192

Middle Eastern (MID)

AF:

0.0601

AC:

337

AN:

5604

European-Non Finnish (NFE)

AF:

0.0499

AC:

54645

AN:

1094048

Other (OTH)

AF:

0.0402

AC:

2403

AN:

59732

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

3051

6102

9152

12203

15254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1958

3916

5874

7832

9790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0376

AC:

5720

AN:

152250

Hom.:

104

Cov.:

AF XY:

0.0374

AC XY:

2783

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0247

AC:

1026

AN:

41544

American (AMR)

AF:

0.0395

AC:

603

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0386

AC:

134

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.0118

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0368

AC:

390

AN:

10612

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0488

AC:

3318

AN:

68004

Other (OTH)

AF:

0.0454

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

290

579

869

1158

1448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0232

Hom.:

Bravo

AF:

0.0362

Asia WGS

AF:

0.0140

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.42

(source)

DANN

Benign

0.41

PhyloP100

-0.39

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over