Genetic Variant NM_032852.4:c.620C>G (chr1-62819230-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032852.4(ATG4C):c.620C>G(p.Ser207Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,342 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S207F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ATG4C
NM_032852.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.300

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATG4C	NM_032852.4 link	c.620C>G	p.Ser207Cys	missense_variant	Exon 5 of 11	ENST00000317868.9	NP_116241.2	Q96DT6A0A384MTY5
ATG4C	NM_178221.3 link	c.620C>G	p.Ser207Cys	missense_variant	Exon 5 of 11		NP_835739.1	Q96DT6A0A384MTY5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATG4C	ENST00000317868.9 link	c.620C>G	p.Ser207Cys	missense_variant	Exon 5 of 11	1	NM_032852.4	ENSP00000322159.4	Q96DT6
ATG4C	ENST00000371120.7 link	c.620C>G	p.Ser207Cys	missense_variant	Exon 5 of 11	1		ENSP00000360161.3	Q96DT6
ATG4C	ENST00000371118.1 link	c.*51C>G		downstream_gene_variant		5		ENSP00000360159.1	A6NGQ4
ATG4C	ENST00000443289.5 link	c.*165C>G		downstream_gene_variant		2		ENSP00000396614.1	C9JC51

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152032

Hom.:

Cov.:

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461310

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726934

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152032

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74256

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.40

T;T

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.72

.;T

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.61

D;D

MetaSVM

Benign

-0.88

MutationAssessor

Pathogenic

3.2

M;M

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.27

Sift

Benign

0.15

T;T

Sift4G

Uncertain

0.043

D;D

Polyphen

1.0

D;D

Vest4

0.57

MutPred

0.58

Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);

MVP

0.64

MPC

0.075

ClinPred

0.72

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.095

gMVP

0.49

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