1-62819021-T-G

Position:

• chr1-62819021-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032852.4(ATG4C):​c.411T>G​(p.Asp137Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000017 in 1,412,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: ATG4C NM_032852.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0510

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053116113).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATG4C	NM_032852.4	c.411T>G	p.Asp137Glu	missense_variant	5/11	ENST00000317868.9	NP_116241.2
ATG4C	NM_178221.3	c.411T>G	p.Asp137Glu	missense_variant	5/11		NP_835739.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATG4C	ENST00000317868.9	c.411T>G	p.Asp137Glu	missense_variant	5/11	1	NM_032852.4	ENSP00000322159.4
ATG4C	ENST00000371120.7	c.411T>G	p.Asp137Glu	missense_variant	5/11	1		ENSP00000360161.3
ATG4C	ENST00000371118.1	c.411T>G	p.Asp137Glu	missense_variant	5/5	5		ENSP00000360159.1
ATG4C	ENST00000443289.5	c.411T>G	p.Asp137Glu	missense_variant	5/5	2		ENSP00000396614.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000170 AC: 24 AN: 1412898 Hom.: 0 Cov.: 31 AF XY: 0.0000158 AC XY: 11 AN XY: 698144

Gnomad4 AFR exome AF: 0.000345

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000131

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000137

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.411T>G (p.D137E) alteration is located in exon 5 (coding exon 4) of the ATG4C gene. This alteration results from a T to G substitution at nucleotide position 411, causing the aspartic acid (D) at amino acid position 137 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Benign	0.82
DEOGEN2	Benign	0.0030	T;T;T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.77	T;.;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.053	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.29	.;N;N;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.47	N;N;N;N
REVEL	Benign	0.048
Sift	Benign	0.92	T;T;T;T
Sift4G	Benign	0.77	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.050, 0.058
MutPred		0.47		Gain of disorder (P = 0.1672);Gain of disorder (P = 0.1672);Gain of disorder (P = 0.1672);Gain of disorder (P = 0.1672);
MVP		0.35
MPC		0.013
ClinPred		0.11	T
GERP RS		2.1
Varity_R		0.040
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs768182891; hg19: chr1-63284692;