Variant 14-50595598-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5

The NM_015915.5(ATL1):c.596T>A(p.Leu199Gln) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 31)

Consequence

ATL1
NM_015915.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.98

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_015915.5

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATL1. . Gene score misZ 2.6313 (greater than the threshold 3.09). Trascript score misZ 3.8383 (greater than threshold 3.09). GenCC has associacion of gene with hereditary sensory and autonomic neuropathy type 1, hereditary spastic paraplegia 3A, neuropathy, hereditary sensory, type 1D.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.922

PP5

Variant 14-50595598-T-A is Pathogenic according to our data. Variant chr14-50595598-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 208489.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ATL1	NM_015915.5 linkuse as main transcript	c.596T>A	p.Leu199Gln	missense_variant	6/14	ENST00000358385.12
ATL1	NM_001127713.1 linkuse as main transcript	c.596T>A	p.Leu199Gln	missense_variant	7/14
ATL1	NM_181598.4 linkuse as main transcript	c.596T>A	p.Leu199Gln	missense_variant	6/13
ATL1	XM_047431430.1 linkuse as main transcript	c.596T>A	p.Leu199Gln	missense_variant	7/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATL1	ENST00000358385.12 linkuse as main transcript	c.596T>A	p.Leu199Gln	missense_variant	6/14	1	NM_015915.5	P3	Q8WXF7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 3A

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Mendelics

Feb 20, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

.;D;D

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;D;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Uncertain

0.18

MutationAssessor

Pathogenic

3.4

M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.3

D;D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D;T

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

0.89

.;P;.

Vest4

0.95

MutPred

0.78

Gain of disorder (P = 0.0426);Gain of disorder (P = 0.0426);.;

MVP

0.93

MPC

1.6

ClinPred

1.0

GERP RS

5.8

Varity_R

0.94

gMVP

0.88

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over