Genetic Variant ATG12:p.Tyr120Ser (chr5-115832606-T-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004707.4(ATG12):c.359A>C(p.Tyr120Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000258 in 931,128 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: 𝑓 0.0000080 ( 0 hom., cov: 25)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

ATG12
NM_004707.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.14

Variant links:

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]

ATG12 links:

LOC124901049 (HGNC:):

LOC124901049 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.766

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATG12	NM_004707.4 link	c.359A>C	p.Tyr120Ser	missense_variant	Exon 3 of 4	ENST00000509910.2	NP_004698.3	O94817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATG12	ENST00000509910.2 link	c.359A>C	p.Tyr120Ser	missense_variant	Exon 3 of 4	1	NM_004707.4	ENSP00000425107.1		O94817-1

Frequencies

GnomAD3 genomes

AF:

0.00000799

AC:

AN:

125186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000307

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000579

AC:

AN:

172860

Hom.:

AF XY:

0.00

AC XY:

AN XY:

96406

show subpopulations

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:

0.0000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000285

AC:

AN:

805942

Hom.:

Cov.:

AF XY:

0.0000361

AC XY:

AN XY:

415770

show subpopulations

Gnomad4 AFR exome

AF:

0.0000623

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000340

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000328

Gnomad4 OTH exome

AF:

0.0000281

GnomAD4 genome

AF:

0.00000799

AC:

AN:

125186

Hom.:

Cov.:

AF XY:

0.0000170

AC XY:

AN XY:

58814

show subpopulations

Gnomad4 AFR

AF:

0.0000307

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000603

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.359A>C (p.Y120S) alteration is located in exon 3 (coding exon 3) of the ATG12 gene. This alteration results from a A to C substitution at nucleotide position 359, causing the tyrosine (Y) at amino acid position 120 to be replaced by a serine (S). 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

0.92

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Benign

0.24

Eigen

Benign

0.12

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.67

M_CAP

Benign

0.014

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.45

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-6.9

REVEL

Benign

0.29

Sift

Uncertain

0.021

Sift4G

Benign

0.081

Vest4

0.79

MVP

0.50

MPC

0.0097

ClinPred

0.86

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over