chr5-115832624-T-C

Variant names:

• chr5-115832624-T-C
• rs773685540
• NM_004707.4:c.341A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004707.4(ATG12):​c.341A>G​(p.Gln114Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000023 in 1,306,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: ATG12 NM_004707.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.80

Genes affected

ATG12 (HGNC:588): (autophagy related 12) Autophagy is a process of bulk protein degradation in which cytoplasmic components, including organelles, are enclosed in double-membrane structures called autophagosomes and delivered to lysosomes or vacuoles for degradation. ATG12 is the human homolog of a yeast protein involved in autophagy (Mizushima et al., 1998 [PubMed 9852036]).[supplied by OMIM, Mar 2008]

LOC124901049 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATG12	NM_004707.4	c.341A>G	p.Gln114Arg	missense_variant	Exon 3 of 4	ENST00000509910.2	NP_004698.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATG12	ENST00000509910.2	c.341A>G	p.Gln114Arg	missense_variant	Exon 3 of 4	1	NM_004707.4	ENSP00000425107.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.00000548 AC: 1 AN: 182440 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 101032

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000110

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000230 AC: 3 AN: 1306174 Hom.: 0 Cov.: 43 AF XY: 0.00000154 AC XY: 1 AN XY: 649700

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000336

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000194

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

Alfa AF: 0.0000355 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.341A>G (p.Q114R) alteration is located in exon 3 (coding exon 3) of the ATG12 gene. This alteration results from a A to G substitution at nucleotide position 341, causing the glutamine (Q) at amino acid position 114 to be replaced by an arginine (R). 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	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.25	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0090	D
Vest4		0.85
MVP		0.60
MPC		0.0054
ClinPred		0.58	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs773685540; hg19: chr5-115168321;