Variant X-108138159-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_052936.5(ATG4A):c.782C>T(p.Pro261Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,208,180 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.0000036 ( 0 hom. 1 hem. )

Consequence

ATG4A
NM_052936.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.81

Variant links:

Genes affected

ATG4A (HGNC:16489): (autophagy related 4A cysteine peptidase) Autophagy is the process by which endogenous proteins and damaged organelles are destroyed intracellularly. Autophagy is postulated to be essential for cell homeostasis and cell remodeling during differentiation, metamorphosis, non-apoptotic cell death, and aging. Reduced levels of autophagy have been described in some malignant tumors, and a role for autophagy in controlling the unregulated cell growth linked to cancer has been proposed. This gene encodes a member of the autophagin protein family. The encoded protein is also designated as a member of the C-54 family of cysteine proteases. [provided by RefSeq, Mar 2016]

ATG4A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.868

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATG4A	NM_052936.5 link	c.782C>T	p.Pro261Leu	missense_variant	Exon 9 of 13	ENST00000372232.8	NP_443168.2	Q8WYN0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATG4A	ENST00000372232.8 link	c.782C>T	p.Pro261Leu	missense_variant	Exon 9 of 13	1	NM_052936.5	ENSP00000361306.3		Q8WYN0-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

111584

Hom.:

Cov.:

AF XY:

0.0000592

AC XY:

AN XY:

33758

show subpopulations

Gnomad AFR

AF:

0.000359

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183323

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67779

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000365

AC:

AN:

1096596

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

361998

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000986

AC:

AN:

111584

Hom.:

Cov.:

AF XY:

0.0000592

AC XY:

AN XY:

33758

show subpopulations

Gnomad4 AFR

AF:

0.000359

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000982

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.782C>T (p.P261L) alteration is located in exon 9 (coding exon 9) of the ATG4A gene. This alteration results from a C to T substitution at nucleotide position 782, causing the proline (P) at amino acid position 261 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

3.9

H;.

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-8.6

D;D

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.79

MVP

0.83

MPC

1.1

ClinPred

1.0

GERP RS

5.4

Varity_R

0.93

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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