1-62819056-G-C

Variant names:

• chr1-62819056-G-C
• NM_032852.4:c.446G>C

Variant summary

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

The NM_032852.4(ATG4C):​c.446G>C​(p.Trp149Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATG4C NM_032852.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.74

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]

ACMG classification

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	c.446G>C	p.Trp149Ser	missense_variant	Exon 5 of 11	ENST00000317868.9	NP_116241.2
ATG4C	NM_178221.3	c.446G>C	p.Trp149Ser	missense_variant	Exon 5 of 11		NP_835739.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATG4C	ENST00000317868.9	c.446G>C	p.Trp149Ser	missense_variant	Exon 5 of 11	1	NM_032852.4	ENSP00000322159.4
ATG4C	ENST00000371120.7	c.446G>C	p.Trp149Ser	missense_variant	Exon 5 of 11	1		ENSP00000360161.3
ATG4C	ENST00000371118.1	c.446G>C	p.Trp149Ser	missense_variant	Exon 5 of 5	5		ENSP00000360159.1
ATG4C	ENST00000443289.5	c.446G>C	p.Trp149Ser	missense_variant	Exon 5 of 5	2		ENSP00000396614.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.446G>C (p.W149S) alteration is located in exon 5 (coding exon 4) of the ATG4C gene. This alteration results from a G to C substitution at nucleotide position 446, causing the tryptophan (W) at amino acid position 149 to be replaced by a serine (S). 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	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;T;T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;.;D;D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.64	D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.8	.;M;M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D;T;T;D
Sift4G	Pathogenic	0.0	D;T;T;T
Polyphen		0.39	.;B;B;.
Vest4		0.61, 0.60
MutPred		0.54		Loss of catalytic residue at W149 (P = 0.0025);Loss of catalytic residue at W149 (P = 0.0025);Loss of catalytic residue at W149 (P = 0.0025);Loss of catalytic residue at W149 (P = 0.0025);
MVP		0.68
MPC		0.094
ClinPred		0.87	D
GERP RS		5.9
Varity_R		0.46
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-63284727;