Variant X-108137806-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000372232.8(ATG4A):c.550A>C(p.Lys184Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000963 in 1,038,452 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.6e-7 ( 0 hom. 0 hem. )

Consequence

ATG4A
ENST00000372232.8 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.96

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33130318).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATG4A	NM_052936.5 linkuse as main transcript	c.550A>C	p.Lys184Gln	missense_variant, splice_region_variant	8/13	ENST00000372232.8	NP_443168.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATG4A	ENST00000372232.8 linkuse as main transcript	c.550A>C	p.Lys184Gln	missense_variant, splice_region_variant	8/13	1	NM_052936.5	ENSP00000361306	P1	Q8WYN0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000750

AC:

AN:

133253

Hom.:

AF XY:

0.00

AC XY:

AN XY:

42933

show subpopulations

Gnomad AFR exome

AF:

0.0000811

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:

9.63e-7

AC:

AN:

1038452

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

332566

show subpopulations

Gnomad4 AFR exome

AF:

0.0000417

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

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2022

The c.550A>C (p.K184Q) alteration is located in exon 8 (coding exon 8) of the ATG4A gene. This alteration results from a A to C substitution at nucleotide position 550, causing the lysine (K) at amino acid position 184 to be replaced by a glutamine (Q). 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

Benign

0.11

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.080

T;.;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.4

L;L;.

MutationTaster

Benign

1.0

D;D;D;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.1

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.17

T;T;T

Polyphen

0.051

B;B;.

Vest4

0.41

MutPred

0.51

Loss of ubiquitination at K184 (P = 0.0183);Loss of ubiquitination at K184 (P = 0.0183);.;

MVP

0.51

MPC

1.2

ClinPred

0.36

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.77

gMVP

0.55

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