1-62816592-C-G

Variant names:

• chr1-62816592-C-G
• NM_032852.4:c.178C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032852.4(ATG4C):​c.178C>G​(p.Pro60Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P60S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATG4C NM_032852.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.695

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09240419).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATG4C	NM_032852.4	c.178C>G	p.Pro60Ala	missense_variant	Exon 4 of 11	ENST00000317868.9	NP_116241.2
ATG4C	NM_178221.3	c.178C>G	p.Pro60Ala	missense_variant	Exon 4 of 11		NP_835739.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATG4C	ENST00000317868.9	c.178C>G	p.Pro60Ala	missense_variant	Exon 4 of 11	1	NM_032852.4	ENSP00000322159.4
ATG4C	ENST00000371120.7	c.178C>G	p.Pro60Ala	missense_variant	Exon 4 of 11	1		ENSP00000360161.3
ATG4C	ENST00000371118.1	c.178C>G	p.Pro60Ala	missense_variant	Exon 4 of 5	5		ENSP00000360159.1
ATG4C	ENST00000443289.5	c.178C>G	p.Pro60Ala	missense_variant	Exon 4 of 5	2		ENSP00000396614.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456612 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724398

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	5.7
DANN	Benign	0.76
DEOGEN2	Benign	0.030	T;T;T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.69	T;.;T;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.092	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	.;M;M;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.014
Sift	Benign	0.052	T;D;D;D
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.13	.;B;B;.
Vest4		0.32, 0.40
MutPred		0.35		Loss of disorder (P = 0.0946);Loss of disorder (P = 0.0946);Loss of disorder (P = 0.0946);Loss of disorder (P = 0.0946);
MVP		0.19
MPC		0.013
ClinPred		0.19	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.044
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr1-63282263;