rs202024659

Variant names:

• chr1-62805193-C-G
• rs202024659
• NM_032852.4:c.98C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-62805193-C-G
• chr1-62805193-C-A
• chr1-62805193-C-T

Variant summary

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

The NM_032852.4(ATG4C):​c.98C>G​(p.Thr33Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000147 in 1,360,510 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: ATG4C NM_032852.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.57
• Publications: 3 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, 0.792

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.98C>G	p.Thr33Arg	missense	Exon 3 of 11	NP_116241.2
	ATG4C	NM_178221.3		c.98C>G	p.Thr33Arg	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.98C>G	p.Thr33Arg	missense	Exon 3 of 11	ENSP00000322159.4	Q96DT6
	ATG4C	ENST00000371120.7	TSL:1	c.98C>G	p.Thr33Arg	missense	Exon 3 of 11	ENSP00000360161.3	Q96DT6
	ATG4C	ENST00000852843.1		c.98C>G	p.Thr33Arg	missense	Exon 3 of 12	ENSP00000522902.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1360510 Hom.: 0 Cov.: 34 AF XY: 0.00000148 AC XY: 1 AN XY: 674752

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27098

American (AMR) AF: 0.0000404 AC: 1 AN: 24758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23220

East Asian (EAS) AF: 0.00 AC: 0 AN: 32948

South Asian (SAS) AF: 0.0000147 AC: 1 AN: 67974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5400

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1072068

Other (OTH) AF: 0.00 AC: 0 AN: 55760

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000037155), which strongly suggests a high chance of mosaicism in these individuals.

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	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.65		Gain of MoRF binding (P = 0.0101)
MVP		0.70
MPC		0.093
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.81
gMVP		0.72
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs202024659; hg19: chr1-63270864;