Genetic Variant ATG4A:p.Arg199Ser (chrX-108137853-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_052936.5(ATG4A):c.597G>T(p.Arg199Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000673 in 1,188,877 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000065 ( 0 hom. 1 hem. )

Consequence

ATG4A
NM_052936.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.443

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03570375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATG4A	NM_052936.5 link	c.597G>T	p.Arg199Ser	missense_variant	Exon 8 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.597G>T	p.Arg199Ser	missense_variant	Exon 8 of 13	1	NM_052936.5	ENSP00000361306.3		Q8WYN0-1

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

111982

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34168

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000127

AC:

AN:

157941

Hom.:

AF XY:

0.0000202

AC XY:

AN XY:

49423

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000276

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000650

AC:

AN:

1076895

Hom.:

Cov.:

AF XY:

0.00000286

AC XY:

AN XY:

349561

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000720

Gnomad4 OTH exome

AF:

0.0000221

GnomAD4 genome

AF:

0.00000893

AC:

AN:

111982

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34168

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 07, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.15

DANN

Benign

0.50

DEOGEN2

Benign

0.040

T;.;.

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.57

T;T;T

M_CAP

Benign

0.0056

MetaRNN

Benign

0.036

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.5

N;N;.

PrimateAI

Benign

0.22

PROVEAN

Benign

1.1

N;N;N

REVEL

Benign

0.031

Sift

Benign

0.85

T;T;T

Sift4G

Benign

0.75

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.057

MutPred

0.40

Loss of solvent accessibility (P = 0.0117);Loss of solvent accessibility (P = 0.0117);.;

MVP

0.32

MPC

0.43

ClinPred

0.018

GERP RS

-4.0

Varity_R

0.11

gMVP

0.15

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

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