dbSNP rs202024659: ATG4C:p.Thr33Lys (chr1-62805193-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_032852.4(ATG4C):c.98C>A(p.Thr33Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000221 in 1,360,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T33R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ATG4C
NM_032852.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.57

Variant links:

Genes affected

ATG4C (HGNC:16040): (autophagy related 4C 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. Alternate transcriptional splice variants, encoding the same protein, have been characterized. [provided by RefSeq, Jul 2008]

ATG4C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATG4C	NM_032852.4 link	c.98C>A	p.Thr33Lys	missense_variant	Exon 3 of 11	ENST00000317868.9	NP_116241.2	Q96DT6A0A384MTY5
ATG4C	NM_178221.3 link	c.98C>A	p.Thr33Lys	missense_variant	Exon 3 of 11		NP_835739.1	Q96DT6A0A384MTY5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATG4C	ENST00000317868.9 link	c.98C>A	p.Thr33Lys	missense_variant	Exon 3 of 11	1	NM_032852.4	ENSP00000322159.4	Q96DT6
ATG4C	ENST00000371120.7 link	c.98C>A	p.Thr33Lys	missense_variant	Exon 3 of 11	1		ENSP00000360161.3	Q96DT6
ATG4C	ENST00000371118.1 link	c.98C>A	p.Thr33Lys	missense_variant	Exon 3 of 5	5		ENSP00000360159.1	A6NGQ4
ATG4C	ENST00000443289.5 link	c.98C>A	p.Thr33Lys	missense_variant	Exon 3 of 5	2		ENSP00000396614.1	C9JC51

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

147170

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000570

AC:

AN:

175290

Hom.:

AF XY:

0.0000103

AC XY:

AN XY:

97172

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:

0.0000113

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000221

AC:

AN:

1360504

Hom.:

Cov.:

AF XY:

0.00000296

AC XY:

AN XY:

674750

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:

0.00000280

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

147254

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71590

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:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T;T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;.;D;D

M_CAP

Benign

0.054

MetaRNN

Pathogenic

0.78

D;D;D;D

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.6

.;M;M;.

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.6

D;D;D;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0050

D;D;D;D

Sift4G

Benign

0.086

T;D;D;T

Polyphen

1.0

.;D;D;.

Vest4

0.76, 0.82

MutPred

0.63

Gain of MoRF binding (P = 0.022);Gain of MoRF binding (P = 0.022);Gain of MoRF binding (P = 0.022);Gain of MoRF binding (P = 0.022);

MVP

0.71

MPC

0.093

ClinPred

0.98

GERP RS

4.6

Varity_R

0.80

gMVP

0.72

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over