NM_052936.5:c.424A>G

Variant names:

• chrX-108134368-A-G
• rs1280412095
• NM_052936.5:c.424A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_052936.5(ATG4A):​c.424A>G​(p.Ile142Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,209,945 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 2 hem.)
• Consequence: ATG4A NM_052936.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.26
• Publications: 0 publications found

Genes affected

ATG4A (HGNC:16489): (autophagy related 4A 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. [provided by RefSeq, Mar 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24580199).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052936.5. 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
	ATG4A	NM_052936.5	MANE Select	c.424A>G	p.Ile142Val	missense	Exon 6 of 13	NP_443168.2
	ATG4A	NM_178270.4		c.424A>G	p.Ile142Val	missense	Exon 6 of 12	NP_840054.1	Q8WYN0-2
	ATG4A	NM_001321287.2		c.193A>G	p.Ile65Val	missense	Exon 7 of 14	NP_001308216.1	Q8WYN0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG4A	ENST00000372232.8	TSL:1 MANE Select	c.424A>G	p.Ile142Val	missense	Exon 6 of 13	ENSP00000361306.3	Q8WYN0-1
	ATG4A	ENST00000345734.7	TSL:1	c.424A>G	p.Ile142Val	missense	Exon 6 of 12	ENSP00000298131.5	Q8WYN0-2
	ATG4A	ENST00000372246.7	TSL:1	n.*582A>G		non_coding_transcript_exon	Exon 7 of 14	ENSP00000361320.3	F8W7J2

Frequencies

GnomAD3 genomes AF: 0.00000889 AC: 1 AN: 112530 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00000548 AC: 1 AN: 182469 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1097415 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 2 AN XY: 362825

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

African (AFR) AF: 0.00 AC: 0 AN: 26380

American (AMR) AF: 0.00 AC: 0 AN: 35129

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19366

East Asian (EAS) AF: 0.00 AC: 0 AN: 30178

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 53969

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841684

Other (OTH) AF: 0.00 AC: 0 AN: 46072

⚠️ 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: 0.00000889 AC: 1 AN: 112530 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34674

African (AFR) AF: 0.0000323 AC: 1 AN: 30955

American (AMR) AF: 0.00 AC: 0 AN: 10635

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3590

South Asian (SAS) AF: 0.00 AC: 0 AN: 2729

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53363

Other (OTH) AF: 0.00 AC: 0 AN: 1509

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

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	Benign	0.059
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.048	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.59	N
PhyloP100		3.3
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.066
Sift	Benign	0.50	T
Sift4G	Benign	0.96	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.53		Loss of methylation at K140 (P = 0.0949)
MVP		0.41
MPC		0.33
ClinPred		0.17	T
GERP RS		4.7
Varity_R		0.19
gMVP		0.23
Mutation Taster		=94/6	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: rs1280412095; hg19: chrX-107377598;