chr1-62819056-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W149C) has been classified as Uncertain significance.

• 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
• Publications: 0 publications found

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]

ENSG00000306496 (HGNC:58931):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.446G>C	p.Trp149Ser	missense	Exon 5 of 11	NP_116241.2
	ATG4C	NM_178221.3		c.446G>C	p.Trp149Ser	missense	Exon 5 of 11	NP_835739.1	A0A384MTY5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG4C	ENST00000317868.9	TSL:1 MANE Select	c.446G>C	p.Trp149Ser	missense	Exon 5 of 11	ENSP00000322159.4	Q96DT6
	ATG4C	ENST00000371120.7	TSL:1	c.446G>C	p.Trp149Ser	missense	Exon 5 of 11	ENSP00000360161.3	Q96DT6
	ATG4C	ENST00000852843.1		c.548G>C	p.Trp183Ser	missense	Exon 6 of 12	ENSP00000522902.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.39	B
Vest4		0.61
MutPred		0.54		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
Mutation Taster		=35/65	disease causing

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

Other links and lift over

hg19: chr1-63284727;