Genetic Variant ATG4C:p.Glu219Asp (chr1-62819267-A-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_032852.4(ATG4C):c.657A>C(p.Glu219Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000905 in 1,613,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

ATG4C
NM_032852.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.00300

Publications

0 publications found

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:

ENSG00000306496 (HGNC:58931):

ENSG00000306496 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023201257).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032852.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG4C	NM_032852.4	MANE Select	c.657A>C	p.Glu219Asp	missense	Exon 5 of 11	NP_116241.2
	ATG4C	NM_178221.3		c.657A>C	p.Glu219Asp	missense	Exon 5 of 11	NP_835739.1	A0A384MTY5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATG4C	ENST00000317868.9	TSL:1 MANE Select	c.657A>C	p.Glu219Asp	missense	Exon 5 of 11	ENSP00000322159.4	Q96DT6
ATG4C	ENST00000371120.7	TSL:1	c.657A>C	p.Glu219Asp	missense	Exon 5 of 11	ENSP00000360161.3	Q96DT6
ATG4C	ENST00000852843.1		c.759A>C	p.Glu253Asp	missense	Exon 6 of 12	ENSP00000522902.1

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

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:

0.000956

GnomAD2 exomes

AF:

0.0000919

AC:

AN:

250148

AF XY:

0.0000740

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.0000582

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1460974

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

726698

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

33442

American (AMR)

AF:

0.0000224

AC:

AN:

44616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.0000233

AC:

AN:

86016

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111662

Other (OTH)

AF:

0.000116

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000460

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

41578

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67968

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000362

Hom.:

Bravo

AF:

0.000529

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.18

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.78

M_CAP

Benign

0.0074

MetaRNN

Benign

0.023

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.0

PhyloP100

0.0030

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.5

REVEL

Benign

0.063

Sift

Benign

0.20

Sift4G

Benign

0.33

Polyphen

0.020

Vest4

0.20

MutPred

0.48

Loss of catalytic residue at E219 (P = 0.0965)

MVP

0.37

MPC

0.013

ClinPred

0.026

GERP RS

-0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.40

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over