3-112538148-C-T

Variant names:

• chr3-112538148-C-T
• NM_022488.5:c.508G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022488.5(ATG3):​c.508G>A​(p.Glu170Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATG3 NM_022488.5 missense, splice_region
• Scores: Splicing: ADA: 0.9239
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.17

Genes affected

ATG3 (HGNC:20962): (autophagy related 3) This gene encodes a ubiquitin-like-conjugating enzyme and is a component of ubiquitination-like systems involved in autophagy, the process of degradation, turnover and recycling of cytoplasmic constituents in eukaryotic cells. This protein is known to play a role in regulation of autophagy during cell death. A pseudogene of this gene is located on chromosome 20. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23884404).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATG3	NM_022488.5	c.508G>A	p.Glu170Lys	missense_variant, splice_region_variant	Exon 8 of 12	ENST00000283290.10	NP_071933.2
ATG3	NM_001278712.2	c.508G>A	p.Glu170Lys	missense_variant, splice_region_variant	Exon 8 of 11		NP_001265641.1
ATG3	XM_011513074.1	c.247G>A	p.Glu83Lys	missense_variant, splice_region_variant	Exon 8 of 12		XP_011511376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATG3	ENST00000283290.10	c.508G>A	p.Glu170Lys	missense_variant, splice_region_variant	Exon 8 of 12	1	NM_022488.5	ENSP00000283290.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.508G>A (p.E170K) alteration is located in exon 8 (coding exon 8) of the ATG3 gene. This alteration results from a G to A substitution at nucleotide position 508, causing the glutamic acid (E) at amino acid position 170 to be replaced by a lysine (K). 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	0.33
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.096
Sift	Benign	0.23	T;T;D
Sift4G	Benign	0.65	T;T;D
Polyphen		0.083	B;B;P
Vest4		0.21
MutPred		0.35		Gain of ubiquitination at E170 (P = 0.0039);Gain of ubiquitination at E170 (P = 0.0039);.;
MVP		0.41
MPC		0.72
ClinPred		0.70	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Pathogenic	0.76
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: chr3-112256995;