chr2-241651275-A-G

Variant names:

• chr2-241651275-A-G
• rs1297451770
• NM_013325.5:c.124A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_013325.5(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. 14/22 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 NM_013325.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013325.5. 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
	ATG4B	NM_013325.5	MANE Select	c.124A>G	p.Ile42Val	missense	Exon 3 of 13	NP_037457.3
	ATG4B	NM_178326.3		c.124A>G	p.Ile42Val	missense	Exon 3 of 13	NP_847896.1	Q9Y4P1-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG4B	ENST00000404914.8	TSL:1 MANE Select	c.124A>G	p.Ile42Val	missense	Exon 3 of 13	ENSP00000384259.3	Q9Y4P1-1
	ATG4B	ENST00000482507.5	TSL:1	n.141A>G		non_coding_transcript_exon	Exon 3 of 13
	ATG4B	ENST00000902606.1		c.307A>G	p.Ile103Val	missense	Exon 4 of 14	ENSP00000572665.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.13
Sift	Benign	0.040	D
Sift4G	Benign	0.092	T
Polyphen		0.20	B
Vest4		0.28
MutPred		0.71		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
Mutation Taster		=74/26	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: rs1297451770; hg19: chr2-242590690;