NM_032852.4:c.146A>C

Variant names:

• chr1-62805241-A-C
• rs770883310
• NM_032852.4:c.146A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032852.4(ATG4C):​c.146A>C​(p.His49Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000712 in 1,515,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: ATG4C NM_032852.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.75
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

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.146A>C	p.His49Pro	missense	Exon 3 of 11	NP_116241.2
	ATG4C	NM_178221.3		c.146A>C	p.His49Pro	missense	Exon 3 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.146A>C	p.His49Pro	missense	Exon 3 of 11	ENSP00000322159.4	Q96DT6
	ATG4C	ENST00000371120.7	TSL:1	c.146A>C	p.His49Pro	missense	Exon 3 of 11	ENSP00000360161.3	Q96DT6
	ATG4C	ENST00000852843.1		c.146A>C	p.His49Pro	missense	Exon 3 of 12	ENSP00000522902.1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151436 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000581 AC: 1 AN: 172242 AF XY: 0.0000104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000784 AC: 107 AN: 1364494 Hom.: 0 Cov.: 33 AF XY: 0.0000812 AC XY: 55 AN XY: 677174

African (AFR) AF: 0.0000367 AC: 1 AN: 27240

American (AMR) AF: 0.00 AC: 0 AN: 24426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23034

East Asian (EAS) AF: 0.00 AC: 0 AN: 33626

South Asian (SAS) AF: 0.00 AC: 0 AN: 68684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5428

European-Non Finnish (NFE) AF: 0.0000958 AC: 103 AN: 1074962

Other (OTH) AF: 0.0000537 AC: 3 AN: 55906

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151436 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73920

African (AFR) AF: 0.00 AC: 0 AN: 41212

American (AMR) AF: 0.00 AC: 0 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67892

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000387 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000825 AC: 1

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	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.018	D
Sift4G	Benign	0.081	T
Polyphen		1.0	D
Vest4		0.83
MutPred		0.49		Loss of sheet (P = 0.1158)
MVP		0.67
MPC		0.093
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.86
gMVP		0.91
Mutation Taster		=40/60	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

dbSNP: rs770883310; hg19: chr1-63270912;