2-241651275-A-G

Position:

• chr2-241651275-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000404914.8(ATG4B):​c.124A>G​(p.Ile42Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I42F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATG4B ENST00000404914.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

Genes affected

ATG4B (HGNC:20790): (autophagy related 4B 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 different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ATG4B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34699667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATG4B	NM_013325.5	c.124A>G	p.Ile42Val	missense_variant	3/13	ENST00000404914.8	NP_037457.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATG4B	ENST00000404914.8	c.124A>G	p.Ile42Val	missense_variant	3/13	1	NM_013325.5	ENSP00000384259.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Aug 11, 2022

The c.124A>G (p.I42V) alteration is located in exon 3 (coding exon 3) of the ATG4B gene. This alteration results from a A to G substitution at nucleotide position 124, causing the isoleucine (I) at amino acid position 42 to be replaced by a valine (V). 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	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.15	.;.;T;.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;D;D;.;D
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.7	M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.86	N;.;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.040	D;.;D;T;D
Sift4G	Benign	0.092	T;T;T;T;D
Polyphen		0.20	.;.;B;.;.
Vest4		0.28
MutPred		0.71		Gain of ubiquitination at K39 (P = 0.1115);Gain of ubiquitination at K39 (P = 0.1115);Gain of ubiquitination at K39 (P = 0.1115);Gain of ubiquitination at K39 (P = 0.1115);Gain of ubiquitination at K39 (P = 0.1115);
MVP		0.34
MPC		0.41
ClinPred		0.79	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.43

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: chr2-242590690;