1-62805225-C-A

Position:

chr1-62805225-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032852.4(ATG4C):c.130C>A(p.Leu44Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000804 in 1,504,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

ATG4C
NM_032852.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.78

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12968716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATG4C	NM_032852.4 linkuse as main transcript	c.130C>A	p.Leu44Ile	missense_variant	3/11	ENST00000317868.9	NP_116241.2	Q96DT6A0A384MTY5
ATG4C	NM_178221.3 linkuse as main transcript	c.130C>A	p.Leu44Ile	missense_variant	3/11		NP_835739.1	Q96DT6A0A384MTY5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ATG4C	ENST00000317868.9 linkuse as main transcript	c.130C>A	p.Leu44Ile	missense_variant	3/11	1	NM_032852.4	ENSP00000322159.4	Q96DT6
ATG4C	ENST00000371120.7 linkuse as main transcript	c.130C>A	p.Leu44Ile	missense_variant	3/11	1		ENSP00000360161.3	Q96DT6
ATG4C	ENST00000371118.1 linkuse as main transcript	c.130C>A	p.Leu44Ile	missense_variant	3/5	5		ENSP00000360159.1	A6NGQ4
ATG4C	ENST00000443289.5 linkuse as main transcript	c.130C>A	p.Leu44Ile	missense_variant	3/5	2		ENSP00000396614.1	C9JC51

Frequencies

GnomAD3 genomes

AF:

0.000482

AC:

AN:

149458

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00175

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:

0.000487

GnomAD3 exomes

AF:

0.0000630

AC:

AN:

174512

Hom.:

AF XY:

0.0000310

AC XY:

AN XY:

96808

show subpopulations

Gnomad AFR exome

AF:

0.000842

Gnomad AMR exome

AF:

0.0000625

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:

0.0000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000362

AC:

AN:

1355044

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

671690

show subpopulations

Gnomad4 AFR exome

AF:

0.00151

Gnomad4 AMR exome

AF:

0.000118

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:

9.36e-7

Gnomad4 OTH exome

AF:

0.0000720

GnomAD4 genome

AF:

0.000481

AC:

AN:

149544

Hom.:

Cov.:

AF XY:

0.000494

AC XY:

AN XY:

72864

show subpopulations

Gnomad4 AFR

AF:

0.00175

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:

0.000483

Alfa

AF:

0.000202

Hom.:

Bravo

AF:

0.000446

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000989

AC:

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 22, 2022

The c.130C>A (p.L44I) alteration is located in exon 3 (coding exon 2) of the ATG4C gene. This alteration results from a C to A substitution at nucleotide position 130, causing the leucine (L) at amino acid position 44 to be replaced by an isoleucine (I). 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

Pathogenic

0.62

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;T;T;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

D;.;D;D

M_CAP

Benign

0.032

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-0.30

MutationAssessor

Uncertain

2.6

.;M;M;.

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Uncertain

0.34

Sift

Uncertain

0.015

D;D;D;D

Sift4G

Uncertain

0.020

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.59, 0.47

MVP

0.58

MPC

0.093

ClinPred

0.14

GERP RS

4.5

Varity_R

0.34

gMVP

0.67

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