2-241659157-A-G

Variant names:

• chr2-241659157-A-G
• NM_013325.5:c.508A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_013325.5(ATG4B):​c.508A>G​(p.Met170Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,438 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ATG4B NM_013325.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATG4B	NM_013325.5	c.508A>G	p.Met170Val	missense_variant	Exon 7 of 13	ENST00000404914.8	NP_037457.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATG4B	ENST00000404914.8	c.508A>G	p.Met170Val	missense_variant	Exon 7 of 13	1	NM_013325.5	ENSP00000384259.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461438 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727002

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.508A>G (p.M170V) alteration is located in exon 7 (coding exon 7) of the ATG4B gene. This alteration results from a A to G substitution at nucleotide position 508, causing the methionine (M) at amino acid position 170 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	0.27
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	.;.;T;.;.;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;.;.;.
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.61	D;D;D;D;D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.2	M;.;M;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D
REVEL	Benign	0.27
Sift	Benign	0.044	D;D;D;T;T;T
Sift4G	Benign	0.11	T;D;T;D;T;T
Polyphen		0.75, 0.62	.;P;P;.;.;.
Vest4		0.87
MutPred		0.44		Loss of stability (P = 0.0707);.;Loss of stability (P = 0.0707);Loss of stability (P = 0.0707);.;.;
MVP		0.69
MPC		0.83
ClinPred		0.94	D
GERP RS		5.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.86
gMVP		0.79

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: chr2-242598572;