Variant X-108131266-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_178271.3(ATG4A):c.-32C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000992 in 1,209,285 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 49 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.000098 ( 0 hom. 45 hem. )

Consequence

ATG4A
NM_178271.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.38

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATG4A	NM_052936.5 link	c.200C>T	p.Thr67Met	missense_variant	Exon 4 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.200C>T	p.Thr67Met	missense_variant	Exon 4 of 13	1	NM_052936.5	ENSP00000361306.3		Q8WYN0-1

Frequencies

GnomAD3 genomes

AF:

0.000116

AC:

AN:

112229

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

34393

show subpopulations

Gnomad AFR

AF:

0.0000970

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000471

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:

0.0000939

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000607

AC:

AN:

181238

Hom.:

AF XY:

0.0000600

AC XY:

AN XY:

66716

show subpopulations

Gnomad AFR exome

AF:

0.0000761

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:

0.000125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000984

AC:

108

AN:

1097003

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

362525

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:

0.000122

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.000107

AC:

AN:

112282

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

34456

show subpopulations

Gnomad4 AFR

AF:

0.0000968

Gnomad4 AMR

AF:

0.000377

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000939

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000102

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.200C>T (p.T67M) alteration is located in exon 4 (coding exon 4) of the ATG4A gene. This alteration results from a C to T substitution at nucleotide position 200, causing the threonine (T) at amino acid position 67 to be replaced by a methionine (M). 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

Uncertain

0.41

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

T;.

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.71

MetaRNN

Uncertain

0.64

D;D

MetaSVM

Uncertain

0.030

MutationAssessor

Pathogenic

2.9

M;M

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-4.2

D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

D;D

Vest4

0.47

MVP

0.60

MPC

1.2

ClinPred

0.71

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.68

gMVP

0.66

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

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