1-62816803-G-T

Variant names:

• chr1-62816803-G-T
• NM_032852.4:c.389G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_032852.4(ATG4C):​c.389G>T​(p.Gly130Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000725 in 1,378,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G130D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: ATG4C NM_032852.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.46

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATG4C	NM_032852.4	c.389G>T	p.Gly130Val	missense_variant	Exon 4 of 11	ENST00000317868.9	NP_116241.2
ATG4C	NM_178221.3	c.389G>T	p.Gly130Val	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.389G>T	p.Gly130Val	missense_variant	Exon 4 of 11	1	NM_032852.4	ENSP00000322159.4
ATG4C	ENST00000371120.7	c.389G>T	p.Gly130Val	missense_variant	Exon 4 of 11	1		ENSP00000360161.3
ATG4C	ENST00000371118.1	c.389G>T	p.Gly130Val	missense_variant	Exon 4 of 5	5		ENSP00000360159.1
ATG4C	ENST00000443289.5	c.389G>T	p.Gly130Val	missense_variant	Exon 4 of 5	2		ENSP00000396614.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1378524 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 681242

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: 9.35e-7

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	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;D;D;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;.;D;D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.058	D
MutationAssessor	Pathogenic	4.0	.;H;H;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.2	D;D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.89, 0.85
MutPred		0.86		Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);
MVP		0.91
MPC		0.093
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.82
gMVP		0.85

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: chr1-63282474;