Genetic Variant ATL1:p.Pro342Ser (chr14-50621876-C-T) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3_Moderate

The NM_015915.5(ATL1):c.1024C>T(p.Pro342Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P342A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ATL1
NM_015915.5 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 7.91

Publications

7 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: 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

ATL1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_015915.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-50621876-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 538579.

PP2

Missense variant in the ATL1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 60 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 2.6313 (below the threshold of 3.09). Trascript score misZ: 3.8383 (above the threshold of 3.09). GenCC associations: The gene is linked to hereditary spastic paraplegia 3A, neuropathy, hereditary sensory, type 1D, hereditary sensory and autonomic neuropathy type 1.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.899

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	HGVSp	Effect	Exon Rank	Protein
ATL1	NM_015915.5	MANE Select	c.1024C>T	p.Pro342Ser	missense	Exon 10 of 14	NP_056999.2
ATL1	NM_001127713.1		c.1024C>T	p.Pro342Ser	missense	Exon 11 of 14	NP_001121185.1
ATL1	NM_181598.4		c.1024C>T	p.Pro342Ser	missense	Exon 10 of 13	NP_853629.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATL1	ENST00000358385.12	TSL:1 MANE Select	c.1024C>T	p.Pro342Ser	missense	Exon 10 of 14	ENSP00000351155.7
ATL1	ENST00000441560.6	TSL:1	c.1024C>T	p.Pro342Ser	missense	Exon 11 of 14	ENSP00000413675.2
ATL1	ENST00000682037.1		c.1024C>T	p.Pro342Ser	missense	Exon 10 of 14	ENSP00000508289.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1448240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721090

African (AFR)

AF:

0.00

AC:

AN:

33160

American (AMR)

AF:

0.00

AC:

AN:

44564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25884

East Asian (EAS)

AF:

0.00

AC:

AN:

39536

South Asian (SAS)

AF:

0.00

AC:

AN:

85778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100406

Other (OTH)

AF:

0.00

AC:

AN:

59950

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 3A

Uncertain:1

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.58

MutationAssessor

Uncertain

2.8

PhyloP100

7.9

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.6

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.77

MutPred

0.67

Gain of loop (P = 0.0079)

MVP

0.95

MPC

1.7

ClinPred

1.0

GERP RS

5.7

Varity_R

0.95

gMVP

0.88

Mutation Taster

=7/93

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over