rs766511615

Variant names:

• chr1-62803859-T-G
• rs766511615
• NM_032852.4:c.73T>G

Your query was ambiguous. Multiple possible variants found:

• chr1-62803859-T-G
• chr1-62803859-T-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_032852.4(ATG4C):​c.73T>G​(p.Tyr25Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000233 in 1,543,170 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: ATG4C NM_032852.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.66
• 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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

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.73T>G	p.Tyr25Asp	missense	Exon 2 of 11	NP_116241.2
	ATG4C	NM_178221.3		c.73T>G	p.Tyr25Asp	missense	Exon 2 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.73T>G	p.Tyr25Asp	missense	Exon 2 of 11	ENSP00000322159.4	Q96DT6
	ATG4C	ENST00000371120.7	TSL:1	c.73T>G	p.Tyr25Asp	missense	Exon 2 of 11	ENSP00000360161.3	Q96DT6
	ATG4C	ENST00000852843.1		c.73T>G	p.Tyr25Asp	missense	Exon 2 of 12	ENSP00000522902.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152066 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000820 AC: 19 AN: 231776 AF XY: 0.0000797

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000473

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000372

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.0000194 AC: 27 AN: 1391104 Hom.: 0 Cov.: 23 AF XY: 0.0000230 AC XY: 16 AN XY: 694840

African (AFR) AF: 0.00 AC: 0 AN: 31008

American (AMR) AF: 0.000456 AC: 18 AN: 39506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24898

East Asian (EAS) AF: 0.00 AC: 0 AN: 38506

South Asian (SAS) AF: 0.00 AC: 0 AN: 80894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5584

European-Non Finnish (NFE) AF: 0.00000661 AC: 7 AN: 1059800

Other (OTH) AF: 0.0000346 AC: 2 AN: 57778

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152066 Hom.: 1 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74286

African (AFR) AF: 0.00 AC: 0 AN: 41418

American (AMR) AF: 0.000589 AC: 9 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.0000247 AC: 3

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	0.97
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.7
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-9.1	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.93
MutPred		0.77		Gain of sheet (P = 0.0221)
MVP		0.68
MPC		0.060
ClinPred		0.71	D
GERP RS		5.0
Varity_R		0.84
gMVP		0.83
Mutation Taster		=11/89	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: rs766511615; hg19: chr1-63269530;