1-62805193-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_032852.4(ATG4C):​c.98C>T​(p.Thr33Met) variant causes a missense change. The variant allele was found at a frequency of 0.000428 in 1,507,640 control chromosomes in the GnomAD database, including 2 homozygotes. 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. T33R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (2 hom.)
• Consequence: ATG4C NM_032852.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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>T	p.Thr33Met	missense	Exon 3 of 11	NP_116241.2
	ATG4C	NM_178221.3		c.98C>T	p.Thr33Met	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>T	p.Thr33Met	missense	Exon 3 of 11	ENSP00000322159.4	Q96DT6
	ATG4C	ENST00000371120.7	TSL:1	c.98C>T	p.Thr33Met	missense	Exon 3 of 11	ENSP00000360161.3	Q96DT6
	ATG4C	ENST00000852843.1		c.98C>T	p.Thr33Met	missense	Exon 3 of 12	ENSP00000522902.1

Frequencies

GnomAD3 genomes AF: 0.000340 AC: 50 AN: 147174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000271

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000634

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000462

Gnomad OTH AF: 0.000495

GnomAD2 exomes AF: 0.000291 AC: 51 AN: 175290 AF XY: 0.000278

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000251

Gnomad ASJ exome AF: 0.000264

Gnomad EAS exome AF: 0.000100

Gnomad FIN exome AF: 0.000148

Gnomad NFE exome AF: 0.000374

Gnomad OTH exome AF: 0.000274

GnomAD4 exome AF: 0.000438 AC: 596 AN: 1360466 Hom.: 2 Cov.: 34 AF XY: 0.000431 AC XY: 291 AN XY: 674722

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

African (AFR) AF: 0.000221 AC: 6 AN: 27098

American (AMR) AF: 0.000242 AC: 6 AN: 24758

Ashkenazi Jewish (ASJ) AF: 0.0000861 AC: 2 AN: 23220

East Asian (EAS) AF: 0.0000304 AC: 1 AN: 32948

South Asian (SAS) AF: 0.000368 AC: 25 AN: 67974

European-Finnish (FIN) AF: 0.000292 AC: 15 AN: 51284

Middle Eastern (MID) AF: 0.00389 AC: 21 AN: 5400

European-Non Finnish (NFE) AF: 0.000455 AC: 488 AN: 1072028

Other (OTH) AF: 0.000574 AC: 32 AN: 55756

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000340 AC: 50 AN: 147174 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 25 AN XY: 71494

African (AFR) AF: 0.000277 AC: 11 AN: 39716

American (AMR) AF: 0.000271 AC: 4 AN: 14748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5102

South Asian (SAS) AF: 0.000634 AC: 3 AN: 4732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 298

European-Non Finnish (NFE) AF: 0.000462 AC: 31 AN: 67102

Other (OTH) AF: 0.000495 AC: 1 AN: 2022

Alfa AF: 0.000344 Hom.: 0

Bravo AF: 0.000336

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000585 AC: 5

ExAC AF: 0.000322 AC: 39

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.79
MVP		0.72
MPC		0.093
ClinPred		0.46	T
GERP RS		4.6
Varity_R		0.47
gMVP		0.61
Mutation Taster		=62/38	polymorphism

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: rs202024659; hg19: chr1-63270864;