5-115841414-G-T

Variant names:

• chr5-115841414-G-T
• rs138567288
• NM_004707.4:c.139C>A

Variant summary

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

The NM_004707.4(ATG12):​c.139C>A​(p.Pro47Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P47S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATG12 NM_004707.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.95
• Publications: 0 publications found

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]

AP3S1 (HGNC:2013): (adaptor related protein complex 3 subunit sigma 1) This gene encodes a subunit of the AP3 adaptor complex. This complex functions in the formation of subcellular vesicles budded from the Golgi body. Several related pseudogenes of this gene have been found. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

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=0.297736).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004707.4. 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
	ATG12	NM_004707.4	MANE Select	c.139C>A	p.Pro47Thr	missense	Exon 1 of 4	NP_004698.3
	ATG12	NM_001277783.2		c.139C>A	p.Pro47Thr	missense	Exon 1 of 3	NP_001264712.1	O94817-4
	ATG12	NR_033362.2		n.152C>A		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG12	ENST00000509910.2	TSL:1 MANE Select	c.139C>A	p.Pro47Thr	missense	Exon 1 of 4	ENSP00000425107.1	O94817-1
	ATG12	ENST00000500945.2	TSL:1	c.139C>A	p.Pro47Thr	missense	Exon 1 of 3	ENSP00000425164.1	O94817-4
	ATG12	ENST00000914944.1		c.139C>A	p.Pro47Thr	missense	Exon 1 of 3	ENSP00000585003.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457624 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725592

African (AFR) AF: 0.00 AC: 0 AN: 32730

American (AMR) AF: 0.00 AC: 0 AN: 42854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111066

Other (OTH) AF: 0.00 AC: 0 AN: 60144

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.14
Sift	Benign	0.18	T
Sift4G	Benign	0.17	T
Polyphen		0.91	P
Vest4		0.52
MVP		0.47
MPC		0.0044
ClinPred		0.94	D
GERP RS		5.1
PromoterAI		-0.031	Neutral
Varity_R		0.32
gMVP		0.48
Mutation Taster		=66/34	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: rs138567288; hg19: chr5-115177111;